This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [I268T] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers.
ClinVar Genomic variation as it relates to human health
NM_000431.4(MVK):c.1129G>A (p.Val377Ile)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(46)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
46
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000431.4(MVK):c.1129G>A (p.Val377Ile)
Variation ID: 11929 Accession: VCV000011929.103
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.11 12: 109596515 (GRCh38) [ NCBI UCSC ] 12: 110034320 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 29, 2015 Dec 28, 2024 Sep 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000431.4:c.1129G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000422.1:p.Val377Ile missense NM_001114185.3:c.1129G>A NP_001107657.1:p.Val377Ile missense NM_001301182.2:c.973G>A NP_001288111.1:p.Val325Ile missense NC_000012.12:g.109596515G>A NC_000012.11:g.110034320G>A NG_007702.1:g.27821G>A LRG_156:g.27821G>A LRG_156t1:c.1129G>A Q03426:p.Val377Ile - Protein change
- V377I, V325I
- Other names
- -
- Canonical SPDI
- NC_000012.12:109596514:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00134
Exome Aggregation Consortium (ExAC) 0.00141
The Genome Aggregation Database (gnomAD) 0.00156
The Genome Aggregation Database (gnomAD), exomes 0.00158
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MVK | - | - |
GRCh38 GRCh37 |
661 | 757 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (17) |
criteria provided, multiple submitters, no conflicts
|
Jul 12, 2024 | RCV000012705.53 | |
| Pathogenic (15) |
criteria provided, multiple submitters, no conflicts
|
Sep 13, 2024 | RCV000221789.62 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2015 | RCV000191108.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000627780.15 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 12, 2024 | RCV000791161.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 5, 2018 | RCV000999977.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 19, 2019 | RCV001270083.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 22, 2021 | RCV002512987.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2022 | RCV002262563.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 22, 2024 | RCV004783724.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2023 | RCV004814886.1 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Mevalonic aciduria (Autosomal recessive inheritance)
Affected status: yes, unknown
Allele origin:
paternal,
germline
|
Baylor Genetics
Study: Adult_WES
Accession: SCV000245511.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [I268T] in a 21-year-old … (more)
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [I268T] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers. (less)
Observation 1:
Number of individuals with the variant: 1
Number of families with the variant: 1
Zygosity: Homozygote, Single Heterozygote, Compound Heterozygote
Age: 20-29 years
Sex: female
Ethnicity/Population group: Hispanic Americans
Observation 2:
Number of individuals with the variant: 23
Zygosity: Homozygote, Single Heterozygote, Compound Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Jun 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279123.13
First in ClinVar: May 29, 2016 Last updated: Jul 01, 2023 |
Comment:
Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999); … (more)
Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23692791, 12634869, 21228398, 23979089, 24561416, 25708585, 30030262, 24177804, 19011501, 34525209, 34809655, 24360083, 24470648, 10369262, 10369261, 15188372, 26300074, 26633545, 26977311, 11313769, 26116953, 15657603, 27899390, 13130485, 26990548, 28638818, 18839211, 24716072, 15536479, 25866490, 24233262, 22038276, 30609409, 26620804, 29290516, 10896296, 30148429, 31474985, 30783801, 31664448, 34573280, 34426522, 34054914, 31589614, 32822427, 32888943, 35418827, 33917151, 35163749, 17105862, 26986117, 35387795, 35753512) (less)
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Pathogenic
(Mar 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538050.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.1129G>A (p.Val377Ile) missense variant in the MVK gene is a known common variant that has been previously reported in numerous individuals affected with Hyper … (more)
The c.1129G>A (p.Val377Ile) missense variant in the MVK gene is a known common variant that has been previously reported in numerous individuals affected with Hyper IgD Syndrome (Houten et al., 1999; Houten et al., 2003; Mandey et al., 2006; Gençpınar et al., 2012; Cantarini et al., 2013; Levy et al., 2013; Shendi et al., 2014; Moussa et al., 2015).This variant has also been reported in trans with other known pathogenic variants (His20Pro, Ile1268Thr, Lys13Aspfs*66, Pro167Leu) (Houten et al.,1999; Gençpınar et al., 2012). Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.221%; 1000 Genomes = NA; and ExAC = 0.196%). A reputable clinical diagnostic laboratory (Baylor Miraca Genetics Laboratories) has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1129G>A (p.Val377Ile) as a recessive Pathogenic variant for Hyper IgD Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing. (less)
|
|
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Pathogenic
(Apr 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hyper-IgD syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595874.1
First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
|
|
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Pathogenic
(Aug 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331859.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
Zygosity: Single Heterozygote
Sex: mixed
|
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Porokeratosis 3, disseminated superficial actinic type
Hyperimmunoglobulin D with periodic fever Mevalonic aciduria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893959.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
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Pathogenic
(Aug 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000375799.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The MVK c.1129G>A (p.Val377Ile) missense variant is very common and occurs in approximately 90% of individuals with hyper IgD syndrome (HIDS) (Messer et al. 2016). … (more)
The MVK c.1129G>A (p.Val377Ile) missense variant is very common and occurs in approximately 90% of individuals with hyper IgD syndrome (HIDS) (Messer et al. 2016). Across a selection of the available literature, the p.Val377Ile variant was reported in a total of 28 symptomatic patients with HIDS, including in eight homozygotes, 16 compound heterozygotes, and four heterozygotes in whom a second variant was not identified (Lainka et al. 2012; Parvaneh et al. 2014; Chandrakasan et al. 2014; Moussa et al. 2015; De Pieri et al. 2015; Messer et al. 2016). The p.Val377Ile variant was also reported in five asymptomatic individuals who were either homozygous or compound heterozygous for the variant (Lainka et al. 2012; Messer et al. 2016), though this is consistent with the mild phenotype and reduced penetrance reported by Houten et al. (2003). Control data are not available in these studies, but the variant is reported at a frequency of 0.00221 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Val377Ile variant is classified as pathogenic for hyper IgD syndrome, though many individuals with this variant may present with a mild phenotype or may be asymptomatic. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
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Pathogenic
(Jan 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928151.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
|
|
|
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Pathogenic
(May 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712172.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Val377Ile variant in MVK has been identified in 0.14% (170/120,578) of chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28934897). This … (more)
The p.Val377Ile variant in MVK has been identified in 0.14% (170/120,578) of chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28934897). This variant is the most frequent pathogenic variant in Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten 1999, Cuis set 2001, Houten 2003). It has been demonstrated to lead to reduced enzymatic ac tivity in vitro (Houten 1999). In summary, this variant meets our criteria to be classified as pathogenic for hyperimmunoglobulinemia D syndrome (HIDS) in an au tosomal recessive manner, based on biallelic observations in patients and functi onal evidence. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138812.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(Jul 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604326.3
First in ClinVar: Sep 30, 2017 Last updated: Feb 09, 2020 |
Comment:
The MVK c.1129G>A;p.Val377Ile variant (rs28934897) is described in the medical literature in both the homozygous and compound heterozygous state in individuals with hyperimmunoglobulin D syndrome … (more)
The MVK c.1129G>A;p.Val377Ile variant (rs28934897) is described in the medical literature in both the homozygous and compound heterozygous state in individuals with hyperimmunoglobulin D syndrome (HIDS) with reduced mevalonate kinase activity and has been implicated as the most common pathogenic HIDS variant (Houten 1999, Houten 2003). The variant is listed in the ClinVar database (Variation ID: 11929) and in the Genome Aggregation Database with an allele frequency of 0.16% (438/275368 alleles). Considering available information, this variant is classified as pathogenic. Pathogenic MVK variants are causative for autosomal recessive hyperimmunoglobulin D syndrome (HIDS, MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Houten SM et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 22(2):175-7. Houten SM et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003 11(2):196-200. (less)
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Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001156405.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of immune system physiology (present) , Rod-cone dystrophy (present)
Zygosity: Compound Heterozygote
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447867.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Fever (present) , Arthralgia/arthritis (present) , Enterocolitis (present)
Sex: male
|
|
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Pathogenic
(Apr 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Porokeratosis 3, multiple types
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448885.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dystonia (present) , Gait disturbance (present) , Parkinsonism with favorable response to dopaminergic medication (present) , Delayed speech and language development (present) , Speech articulation … (more)
Dystonia (present) , Gait disturbance (present) , Parkinsonism with favorable response to dopaminergic medication (present) , Delayed speech and language development (present) , Speech articulation difficulties (present) , Anxiety (present) , Dysphagia (present) , Ptosis (present) , Constipation (present) (less)
Sex: male
|
|
|
Likely pathogenic
(Apr 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366331.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3.
|
|
|
Pathogenic
(Jun 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520663.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Jan 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001736848.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Strabismus (present) , Cataract (present) , Cafe-au-lait spot (present) , Global developmental delay (present) , Cerebellar atrophy (present) , Dystonic disorder (present) , Flexion contracture … (more)
Strabismus (present) , Cataract (present) , Cafe-au-lait spot (present) , Global developmental delay (present) , Cerebellar atrophy (present) , Dystonic disorder (present) , Flexion contracture (present) , Pes planus (present) , Progressive cerebellar ataxia (present) , Generalized non-motor (absence) seizure (present) , Abnormal midbrain morphology (present) , Recurrent oral herpes (present) (less)
Zygosity: Homozygote
Age: 10-19 years
Sex: male
Ethnicity/Population group: Unspecified
Tissue: blood
|
|
|
Likely pathogenic
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
germline
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002104233.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: male
|
|
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Pathogenic
(Jun 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
MVK-related disorder
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002526420.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.1129G>A;p.(Val377Ile) missense change has been observed in affected individual(s)(PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PS4. The p.(Val377Ile) was detected in trans with a … (more)
The c.1129G>A;p.(Val377Ile) missense change has been observed in affected individual(s)(PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PS4. The p.(Val377Ile) was detected in trans with a Pathogenic variant (PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32822427; 17105862) - PP1 andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Pathogenic (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002542319.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818165.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
|
Pathogenic
(Aug 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807561.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PP1 supporting
Number of individuals with the variant: 1
Clinical Features:
Primary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Obesity (present) , Class III obesity (present) , Hyperemesis gravidarum (present) , … (more)
Primary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Obesity (present) , Class III obesity (present) , Hyperemesis gravidarum (present) , Increased body weight (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928976.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: MVK c.1129G>A (p.Val377Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: MVK c.1129G>A (p.Val377Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249414 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database. c.1129G>A has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (HIDS), including in cases where it was in trans with a pathogenic variant and it has been found to segregate with disease (e.g. Houten_1999, Cuisset_2001, Govindaraj_2020). It is reportedly the most frequently occurring variant identified in HIDS patients (Houten_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an MK activity of approximately 40% of WT in E.coli lysates and that it was undetectable by immunoblot in fibroblast lysates from HIDS patients, suggesting it also impacts protein stability (Houten_1999). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and the majority classified it as pathogenic (n=27)/likely pathogenic (n=2), with the remaining classifying it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperimmunoglobulin D with periodic fever
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004031068.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Zygosity: Single Heterozygote
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Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017646.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 12, 2024)
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criteria provided, single submitter
Method: clinical testing
|
MVK-related disorder
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000930436.3
First in ClinVar: Aug 04, 2019 Last updated: Feb 20, 2024 |
Geographic origin: Iran
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Mevalonic aciduria
Hyperimmunoglobulin D with periodic fever Porokeratosis 3, disseminated superficial actinic type
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000634151.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). This variant is present in population databases (rs28934897, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 10369261, 11313769, 12634869, 15536479, 26977311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806825.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003740446.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1129G>A (p.V377I) alteration is located in exon 11 (coding exon 10) of the MVK gene. This alteration results from a G to A substitution … (more)
The c.1129G>A (p.V377I) alteration is located in exon 11 (coding exon 10) of the MVK gene. This alteration results from a G to A substitution at nucleotide position 1129, causing the valine (V) at amino acid position 377 to be replaced by an isoleucine (I). Based on the available evidence, this variant is pathogenic for mevalonate kinase deficiency (AR); however, it is unlikely to be causative of MVK-related porokeratosis (AD). Based on data from the Genome Aggregation Database (gnomAD), the MVK c.1129G>A alteration was observed in 0.16% (443/280790) of total alleles studied, with a frequency of 0.24% (303/128360) in the European (non-Finnish) subpopulation. This common mutation has been reported in individuals with clinical and biochemical features consistent with mevalonate kinase deficiency in both the homozygous and compound heterozygous state (Cuisset, 2001; Drenth, 1999; Houten, 1999; Munoz, 2019); however, asymptomatic individuals have also been reported (Lainka, 2012; Messer, 2016). Functional studies showed that this alteration results in reduced enzyme activity (Houten, 1999; Messer, 2016). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005071253.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
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Pathogenic
(Oct 14, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199301.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Sep 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246722.27
First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024 |
Comment:
MVK: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Number of individuals with the variant: 22
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Pathogenic
(Sep 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716138.5
First in ClinVar: Jun 15, 2021 Last updated: Dec 28, 2024 |
Comment:
PP4, PM3, PS3, PS4
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Pathogenic
(Jul 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
maternal
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV005367959.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
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Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mevalonic aciduria
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397680.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1129 of the coding sequence of the MVK gene that results in a valine … (more)
This sequence variant is a single nucleotide substitution (G>A) at position 1129 of the coding sequence of the MVK gene that results in a valine to isoleucine amino acid change at residue 377 of the mevalonate kinase protein. This is a previously reported variant (ClinVar 11929) that has been observed in a homozygous or compound heterozygous state in individuals affected by hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) and MK enzyme deficiency (MKD) (PMID: 10369261, 10369262, 10896296, 11313769, 12444096, 15536479, 17105862, 22038276, 23979089, 24360083, 24177804, 24233262, 24470648, 24561416, 25708585, 25866490, 26986117, 27213830, 31474985, 32822427, 33917151, 34525209, 34809655, 35387795). Additionally, the homozygous state of this variant is predicted to have variable penetrance of disease (PMID: 12634869, 25708585). This variant is present in 3382 of 1612856 alleles (0.2097%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Val377 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have found reduced or undetectable mevalonate kinase activity and MK protein expression in affected individuals (PMID: 10369261). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BP4, PM3, PP1, PS3, PS4 (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Mevalonic aciduria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399255.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hyper-IgD syndrome (MIM#260920), mevalonic aciduria (MIM#610377) and autosomal dominant porokeratosis 3, multiple types (MIM#175900) (DECIPHER). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported for both conditions. Autosomal dominant porokeratosis 3, multiple types (MIM#175900) may only manifest due to additional circumstances such as environmental factors (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32822427). This gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (221 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common pathogenic variant in the MVK gene and is associated with hyper-IgD syndrome (Infevers database). There are many unrelated patients affected with mevalonate kinase deficiency or hyper-IgD syndrome who were identified as compound heterozygous or homozygous for this variant (ClinVar, PMID: 32822427). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Immunoblot analysis of patient lymphocytes showed minimal MK activity (PMID: 10369261). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 01, 2013)
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no assertion criteria provided
Method: literature only
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HYPER-IgD SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032940.6
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022 |
Comment on evidence:
In 4 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found a 1129G-A transition, resulting in a val377-to-ile amino acid substitution. In … (more)
In 4 patients with the hyper-IgD syndrome (HIDS; 260920), Houten et al. (1999) found a 1129G-A transition, resulting in a val377-to-ile amino acid substitution. In 3 of the 4 patients, V377I was present in compound heterozygous state; in the fourth patient, V377I appeared to be present in homozygous state. The V377I mutation was found in homozygous state in a family with HIDS studied by Drenth et al. (1999). In 16 unrelated patients with HIDS, Houten et al. (2001) detected the V377I mutation, including one sibship with homozygosity. Cuisset et al. (2001) detected the V377I mutation in 20 of 25 unrelated patients with HIDS, the majority of whom were of Dutch origin. D'Osualdo et al. (2005) identified the V377I mutation in 50% of mutant alleles in 15 unrelated Italian patients with HIDS. In 2 patients the V377I mutation was found in homozygous state. In a 14-month-old girl and an unrelated 7-month-old boy with HIDS, Levy et al. (2013) identified the V377I mutation in the MVK gene in compound heterozygous state with a tyr116-to-his (Y116H; 251170.0020) mutation in the girl and a gly326-to-arg (G326R; 251170.0021) mutation in the boy. The mutations were identified by sequencing of the MVK gene, and the parents of both patients were mutation carriers. MVK enzyme activity in patient lymphocytes was below 1%. The clinical features in both patients included recurrent febrile episodes and very-early-onset inflammatory bowel disease (VEOIBD). In a 2-year-old girl, born of consanguineous parents, with HIDS, Brito et al. (2022) identified homozygosity for the V377I mutation in the MVK gene. The mutation, which was identified by next-generation sequencing of a panel of genes associated with autoinflammatory disease, was present in heterozygous state in the parents. The patient's clinical features included recurrent fevers, lymphadenopathy, macular skin rash, abdominal pain, and aphthous ulcers. She had elevated mevalonic acid in the urine when she was experiencing a flare of disease, but not between flares. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548926.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MVK p.Val325Ile variant was identified in 23 of 58 proband chromosomes (frequency: 0.43) from individuals or families with hyperimmunoglobulinaemia D and periodic fever syndrome … (more)
The MVK p.Val325Ile variant was identified in 23 of 58 proband chromosomes (frequency: 0.43) from individuals or families with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten_1999_PMID:10369261; Cuisset_2001_PMID:11313769). The variant was also identified in dbSNP (ID: rs28934897), ClinVar (classified as pathogenic by Invitae, GeneDx and eight other laboratories) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 443 of 280790 chromosomes at a frequency of 0.001578 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 303 of 128360 chromosomes (freq: 0.002361), Latino in 50 of 35436 chromosomes (freq: 0.001411), European (Finnish) in 33 of 23962 chromosomes (freq: 0.001377), Other in 9 of 7198 chromosomes (freq: 0.00125), South Asian in 28 of 30616 chromosomes (freq: 0.000915), Ashkenazi Jewish in 8 of 10360 chromosomes (freq: 0.000772), African in 10 of 24932 chromosomes (freq: 0.000401), and East Asian in 2 of 19926 chromosomes (freq: 0.0001). The V325I variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val325 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However, functional studies expressing cDNA constructs containing the V325I variant in E. coli have demonstrated decreased mevalonate kinase (MK) protein activity compared to wildtype (Houten_1999_PMID:10369261). Decreased MK activity was also found in lymphocytes and fibroblasts from patients with the V325I variant (Houten_1999_PMID:10369261). Interestingly, this variant has been reported in the homozygous state in two sisters, one affected with HIDS and the other who was asymptomatic, therefore suggesting that other genetic factors may influence the presentation of HIDS in individuals with the V325I variant (Messer_2016_PMID:26977311). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740681.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918026.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927500.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957696.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968606.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(May 01, 2022)
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no assertion criteria provided
Method: clinical testing
|
Hyperimmunoglobulin D with periodic fever
Affected status: yes
Allele origin:
germline
|
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573426.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
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Pathogenic
(Feb 08, 2024)
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no assertion criteria provided
Method: clinical testing
|
MVK-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004103055.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MVK c.1129G>A variant is predicted to result in the amino acid substitution p.Val377Ile. This is a well-documented pathogenic variant for Hyper-IgD syndrome (HIDS) and … (more)
The MVK c.1129G>A variant is predicted to result in the amino acid substitution p.Val377Ile. This is a well-documented pathogenic variant for Hyper-IgD syndrome (HIDS) and has been reported in ~90% of the HIDS cases, both in the homozygous and compound heterozygous states (Messer et al. 2016. PubMed ID: 26977311; Schlabe et al. 2016. PubMed ID: 27899390; Houten et al. 2003. PubMed ID: 12634869). Although, there are occasional reports of this variant in patients with mevalonic aciduria (MA) (Favier and Schulert 2016. PubMed ID: 27499643), functional studies did not indicate a profound enzyme deficiency as expected in patients with MA (Cuisset et al. 2001. PubMed ID: 11313769). In addition, this variant is known for its reduced penetrance, leading to a mild or absent phenotype (Houten et al. 2003. PubMed ID: 12634869). This variant is reported in 0.24% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is classified as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/11929/). Taken together, this variant is considered a pathogenic variant for HIDS, but its role in mevalonic aciduria is uncertain. (less)
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not provided
(-)
|
no classification provided
Method: phenotyping only
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Hyperimmunoglobulin D with periodic fever
Porokeratosis 3, disseminated superficial actinic type Mevalonic aciduria
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
maternal
|
GenomeConnect - Brain Gene Registry
Accession: SCV003931223.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory … (more)
Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Failure to thrive (present)
Indication for testing: Diagnostic
Zygosity: Single Heterozygote
Age: 0-9 years
Sex: female
Method: Exome Sequencing
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2016-12-06
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23692791, 12634869, 21228398, 23979089, 24561416, 25708585, 30030262, 24177804, 19011501, 34525209, 34809655, 24360083, 24470648, 10369262, 10369261, 15188372, 26300074, 26633545, 26977311, 11313769, 26116953, 15657603, 27899390, 13130485, 26990548, 28638818, 18839211, 24716072, 15536479, 25866490, 24233262, 22038276, 30609409, 26620804, 29290516, 10896296, 30148429, 31474985, 30783801, 31664448, 34573280, 34426522, 34054914, 31589614, 32822427, 32888943, 35418827, 33917151, 35163749, 17105862, 26986117, 35387795, 35753512)
Comment:
The c.1129G>A (p.Val377Ile) missense variant in the MVK gene is a known common variant that has been previously reported in numerous individuals affected with Hyper IgD Syndrome (Houten et al., 1999; Houten et al., 2003; Mandey et al., 2006; Gençpınar et al., 2012; Cantarini et al., 2013; Levy et al., 2013; Shendi et al., 2014; Moussa et al., 2015).This variant has also been reported in trans with other known pathogenic variants (His20Pro, Ile1268Thr, Lys13Aspfs*66, Pro167Leu) (Houten et al.,1999; Gençpınar et al., 2012). Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.221%; 1000 Genomes = NA; and ExAC = 0.196%). A reputable clinical diagnostic laboratory (Baylor Miraca Genetics Laboratories) has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1129G>A (p.Val377Ile) as a recessive Pathogenic variant for Hyper IgD Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing.
Comment:
The MVK c.1129G>A (p.Val377Ile) missense variant is very common and occurs in approximately 90% of individuals with hyper IgD syndrome (HIDS) (Messer et al. 2016). Across a selection of the available literature, the p.Val377Ile variant was reported in a total of 28 symptomatic patients with HIDS, including in eight homozygotes, 16 compound heterozygotes, and four heterozygotes in whom a second variant was not identified (Lainka et al. 2012; Parvaneh et al. 2014; Chandrakasan et al. 2014; Moussa et al. 2015; De Pieri et al. 2015; Messer et al. 2016). The p.Val377Ile variant was also reported in five asymptomatic individuals who were either homozygous or compound heterozygous for the variant (Lainka et al. 2012; Messer et al. 2016), though this is consistent with the mild phenotype and reduced penetrance reported by Houten et al. (2003). Control data are not available in these studies, but the variant is reported at a frequency of 0.00221 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Val377Ile variant is classified as pathogenic for hyper IgD syndrome, though many individuals with this variant may present with a mild phenotype or may be asymptomatic. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Val377Ile variant in MVK has been identified in 0.14% (170/120,578) of chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28934897). This variant is the most frequent pathogenic variant in Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten 1999, Cuis set 2001, Houten 2003). It has been demonstrated to lead to reduced enzymatic ac tivity in vitro (Houten 1999). In summary, this variant meets our criteria to be classified as pathogenic for hyperimmunoglobulinemia D syndrome (HIDS) in an au tosomal recessive manner, based on biallelic observations in patients and functi onal evidence.
Comment:
The MVK c.1129G>A;p.Val377Ile variant (rs28934897) is described in the medical literature in both the homozygous and compound heterozygous state in individuals with hyperimmunoglobulin D syndrome (HIDS) with reduced mevalonate kinase activity and has been implicated as the most common pathogenic HIDS variant (Houten 1999, Houten 2003). The variant is listed in the ClinVar database (Variation ID: 11929) and in the Genome Aggregation Database with an allele frequency of 0.16% (438/275368 alleles). Considering available information, this variant is classified as pathogenic. Pathogenic MVK variants are causative for autosomal recessive hyperimmunoglobulin D syndrome (HIDS, MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Houten SM et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 22(2):175-7. Houten SM et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003 11(2):196-200.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.1129G>A;p.(Val377Ile) missense change has been observed in affected individual(s)(PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PS4. The p.(Val377Ile) was detected in trans with a Pathogenic variant (PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32822427; 17105862) - PP1 andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PP1 supporting
Comment:
Variant summary: MVK c.1129G>A (p.Val377Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249414 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database. c.1129G>A has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (HIDS), including in cases where it was in trans with a pathogenic variant and it has been found to segregate with disease (e.g. Houten_1999, Cuisset_2001, Govindaraj_2020). It is reportedly the most frequently occurring variant identified in HIDS patients (Houten_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an MK activity of approximately 40% of WT in E.coli lysates and that it was undetectable by immunoblot in fibroblast lysates from HIDS patients, suggesting it also impacts protein stability (Houten_1999). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and the majority classified it as pathogenic (n=27)/likely pathogenic (n=2), with the remaining classifying it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). This variant is present in population databases (rs28934897, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 10369261, 11313769, 12634869, 15536479, 26977311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1129G>A (p.V377I) alteration is located in exon 11 (coding exon 10) of the MVK gene. This alteration results from a G to A substitution at nucleotide position 1129, causing the valine (V) at amino acid position 377 to be replaced by an isoleucine (I). Based on the available evidence, this variant is pathogenic for mevalonate kinase deficiency (AR); however, it is unlikely to be causative of MVK-related porokeratosis (AD). Based on data from the Genome Aggregation Database (gnomAD), the MVK c.1129G>A alteration was observed in 0.16% (443/280790) of total alleles studied, with a frequency of 0.24% (303/128360) in the European (non-Finnish) subpopulation. This common mutation has been reported in individuals with clinical and biochemical features consistent with mevalonate kinase deficiency in both the homozygous and compound heterozygous state (Cuisset, 2001; Drenth, 1999; Houten, 1999; Munoz, 2019); however, asymptomatic individuals have also been reported (Lainka, 2012; Messer, 2016). Functional studies showed that this alteration results in reduced enzyme activity (Houten, 1999; Messer, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
MVK: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Comment:
PP4, PM3, PS3, PS4
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1129 of the coding sequence of the MVK gene that results in a valine to isoleucine amino acid change at residue 377 of the mevalonate kinase protein. This is a previously reported variant (ClinVar 11929) that has been observed in a homozygous or compound heterozygous state in individuals affected by hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) and MK enzyme deficiency (MKD) (PMID: 10369261, 10369262, 10896296, 11313769, 12444096, 15536479, 17105862, 22038276, 23979089, 24360083, 24177804, 24233262, 24470648, 24561416, 25708585, 25866490, 26986117, 27213830, 31474985, 32822427, 33917151, 34525209, 34809655, 35387795). Additionally, the homozygous state of this variant is predicted to have variable penetrance of disease (PMID: 12634869, 25708585). This variant is present in 3382 of 1612856 alleles (0.2097%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Val377 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have found reduced or undetectable mevalonate kinase activity and MK protein expression in affected individuals (PMID: 10369261). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BP4, PM3, PP1, PS3, PS4
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hyper-IgD syndrome (MIM#260920), mevalonic aciduria (MIM#610377) and autosomal dominant porokeratosis 3, multiple types (MIM#175900) (DECIPHER). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported for both conditions. Autosomal dominant porokeratosis 3, multiple types (MIM#175900) may only manifest due to additional circumstances such as environmental factors (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32822427). This gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (221 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common pathogenic variant in the MVK gene and is associated with hyper-IgD syndrome (Infevers database). There are many unrelated patients affected with mevalonate kinase deficiency or hyper-IgD syndrome who were identified as compound heterozygous or homozygous for this variant (ClinVar, PMID: 32822427). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Immunoblot analysis of patient lymphocytes showed minimal MK activity (PMID: 10369261). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The MVK p.Val325Ile variant was identified in 23 of 58 proband chromosomes (frequency: 0.43) from individuals or families with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten_1999_PMID:10369261; Cuisset_2001_PMID:11313769). The variant was also identified in dbSNP (ID: rs28934897), ClinVar (classified as pathogenic by Invitae, GeneDx and eight other laboratories) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 443 of 280790 chromosomes at a frequency of 0.001578 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 303 of 128360 chromosomes (freq: 0.002361), Latino in 50 of 35436 chromosomes (freq: 0.001411), European (Finnish) in 33 of 23962 chromosomes (freq: 0.001377), Other in 9 of 7198 chromosomes (freq: 0.00125), South Asian in 28 of 30616 chromosomes (freq: 0.000915), Ashkenazi Jewish in 8 of 10360 chromosomes (freq: 0.000772), African in 10 of 24932 chromosomes (freq: 0.000401), and East Asian in 2 of 19926 chromosomes (freq: 0.0001). The V325I variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val325 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However, functional studies expressing cDNA constructs containing the V325I variant in E. coli have demonstrated decreased mevalonate kinase (MK) protein activity compared to wildtype (Houten_1999_PMID:10369261). Decreased MK activity was also found in lymphocytes and fibroblasts from patients with the V325I variant (Houten_1999_PMID:10369261). Interestingly, this variant has been reported in the homozygous state in two sisters, one affected with HIDS and the other who was asymptomatic, therefore suggesting that other genetic factors may influence the presentation of HIDS in individuals with the V325I variant (Messer_2016_PMID:26977311). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The MVK c.1129G>A variant is predicted to result in the amino acid substitution p.Val377Ile. This is a well-documented pathogenic variant for Hyper-IgD syndrome (HIDS) and has been reported in ~90% of the HIDS cases, both in the homozygous and compound heterozygous states (Messer et al. 2016. PubMed ID: 26977311; Schlabe et al. 2016. PubMed ID: 27899390; Houten et al. 2003. PubMed ID: 12634869). Although, there are occasional reports of this variant in patients with mevalonic aciduria (MA) (Favier and Schulert 2016. PubMed ID: 27499643), functional studies did not indicate a profound enzyme deficiency as expected in patients with MA (Cuisset et al. 2001. PubMed ID: 11313769). In addition, this variant is known for its reduced penetrance, leading to a mild or absent phenotype (Houten et al. 2003. PubMed ID: 12634869). This variant is reported in 0.24% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is classified as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/11929/). Taken together, this variant is considered a pathogenic variant for HIDS, but its role in mevalonic aciduria is uncertain.
Comment:
Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [I268T] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers.
Comment:
Published functional studies indicate that p.(V377I) leads to a decrease in enzyme activity and decreased stability when expressed in E. coli (Houten et al., 1999); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23692791, 12634869, 21228398, 23979089, 24561416, 25708585, 30030262, 24177804, 19011501, 34525209, 34809655, 24360083, 24470648, 10369262, 10369261, 15188372, 26300074, 26633545, 26977311, 11313769, 26116953, 15657603, 27899390, 13130485, 26990548, 28638818, 18839211, 24716072, 15536479, 25866490, 24233262, 22038276, 30609409, 26620804, 29290516, 10896296, 30148429, 31474985, 30783801, 31664448, 34573280, 34426522, 34054914, 31589614, 32822427, 32888943, 35418827, 33917151, 35163749, 17105862, 26986117, 35387795, 35753512)
Comment:
The c.1129G>A (p.Val377Ile) missense variant in the MVK gene is a known common variant that has been previously reported in numerous individuals affected with Hyper IgD Syndrome (Houten et al., 1999; Houten et al., 2003; Mandey et al., 2006; Gençpınar et al., 2012; Cantarini et al., 2013; Levy et al., 2013; Shendi et al., 2014; Moussa et al., 2015).This variant has also been reported in trans with other known pathogenic variants (His20Pro, Ile1268Thr, Lys13Aspfs*66, Pro167Leu) (Houten et al.,1999; Gençpınar et al., 2012). Functional studies have shown reduced or undetectable mevalonate kinase activity and protein expression in affected individuals, indicating this variant likely affects protein stability and function (Houten et al., 1999). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.221%; 1000 Genomes = NA; and ExAC = 0.196%). A reputable clinical diagnostic laboratory (Baylor Miraca Genetics Laboratories) has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1129G>A (p.Val377Ile) as a recessive Pathogenic variant for Hyper IgD Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing.
Comment:
The MVK c.1129G>A (p.Val377Ile) missense variant is very common and occurs in approximately 90% of individuals with hyper IgD syndrome (HIDS) (Messer et al. 2016). Across a selection of the available literature, the p.Val377Ile variant was reported in a total of 28 symptomatic patients with HIDS, including in eight homozygotes, 16 compound heterozygotes, and four heterozygotes in whom a second variant was not identified (Lainka et al. 2012; Parvaneh et al. 2014; Chandrakasan et al. 2014; Moussa et al. 2015; De Pieri et al. 2015; Messer et al. 2016). The p.Val377Ile variant was also reported in five asymptomatic individuals who were either homozygous or compound heterozygous for the variant (Lainka et al. 2012; Messer et al. 2016), though this is consistent with the mild phenotype and reduced penetrance reported by Houten et al. (2003). Control data are not available in these studies, but the variant is reported at a frequency of 0.00221 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Val377Ile variant is classified as pathogenic for hyper IgD syndrome, though many individuals with this variant may present with a mild phenotype or may be asymptomatic. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Val377Ile variant in MVK has been identified in 0.14% (170/120,578) of chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28934897). This variant is the most frequent pathogenic variant in Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten 1999, Cuis set 2001, Houten 2003). It has been demonstrated to lead to reduced enzymatic ac tivity in vitro (Houten 1999). In summary, this variant meets our criteria to be classified as pathogenic for hyperimmunoglobulinemia D syndrome (HIDS) in an au tosomal recessive manner, based on biallelic observations in patients and functi onal evidence.
Comment:
The MVK c.1129G>A;p.Val377Ile variant (rs28934897) is described in the medical literature in both the homozygous and compound heterozygous state in individuals with hyperimmunoglobulin D syndrome (HIDS) with reduced mevalonate kinase activity and has been implicated as the most common pathogenic HIDS variant (Houten 1999, Houten 2003). The variant is listed in the ClinVar database (Variation ID: 11929) and in the Genome Aggregation Database with an allele frequency of 0.16% (438/275368 alleles). Considering available information, this variant is classified as pathogenic. Pathogenic MVK variants are causative for autosomal recessive hyperimmunoglobulin D syndrome (HIDS, MIM: 260920) and mevalonic aciduria (MIM: 610377). References: Houten SM et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 22(2):175-7. Houten SM et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003 11(2):196-200.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.1129G>A;p.(Val377Ile) missense change has been observed in affected individual(s)(PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PS4. The p.(Val377Ile) was detected in trans with a Pathogenic variant (PMID: 33917151; 26986117; 15536479; 32822427; 17105862) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32822427; 17105862) - PP1 andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PP1 supporting
Comment:
Variant summary: MVK c.1129G>A (p.Val377Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249414 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database. c.1129G>A has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (HIDS), including in cases where it was in trans with a pathogenic variant and it has been found to segregate with disease (e.g. Houten_1999, Cuisset_2001, Govindaraj_2020). It is reportedly the most frequently occurring variant identified in HIDS patients (Houten_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an MK activity of approximately 40% of WT in E.coli lysates and that it was undetectable by immunoblot in fibroblast lysates from HIDS patients, suggesting it also impacts protein stability (Houten_1999). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and the majority classified it as pathogenic (n=27)/likely pathogenic (n=2), with the remaining classifying it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). This variant is present in population databases (rs28934897, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 10369261, 11313769, 12634869, 15536479, 26977311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1129G>A (p.V377I) alteration is located in exon 11 (coding exon 10) of the MVK gene. This alteration results from a G to A substitution at nucleotide position 1129, causing the valine (V) at amino acid position 377 to be replaced by an isoleucine (I). Based on the available evidence, this variant is pathogenic for mevalonate kinase deficiency (AR); however, it is unlikely to be causative of MVK-related porokeratosis (AD). Based on data from the Genome Aggregation Database (gnomAD), the MVK c.1129G>A alteration was observed in 0.16% (443/280790) of total alleles studied, with a frequency of 0.24% (303/128360) in the European (non-Finnish) subpopulation. This common mutation has been reported in individuals with clinical and biochemical features consistent with mevalonate kinase deficiency in both the homozygous and compound heterozygous state (Cuisset, 2001; Drenth, 1999; Houten, 1999; Munoz, 2019); however, asymptomatic individuals have also been reported (Lainka, 2012; Messer, 2016). Functional studies showed that this alteration results in reduced enzyme activity (Houten, 1999; Messer, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
MVK: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Comment:
PP4, PM3, PS3, PS4
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1129 of the coding sequence of the MVK gene that results in a valine to isoleucine amino acid change at residue 377 of the mevalonate kinase protein. This is a previously reported variant (ClinVar 11929) that has been observed in a homozygous or compound heterozygous state in individuals affected by hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) and MK enzyme deficiency (MKD) (PMID: 10369261, 10369262, 10896296, 11313769, 12444096, 15536479, 17105862, 22038276, 23979089, 24360083, 24177804, 24233262, 24470648, 24561416, 25708585, 25866490, 26986117, 27213830, 31474985, 32822427, 33917151, 34525209, 34809655, 35387795). Additionally, the homozygous state of this variant is predicted to have variable penetrance of disease (PMID: 12634869, 25708585). This variant is present in 3382 of 1612856 alleles (0.2097%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Val377 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have found reduced or undetectable mevalonate kinase activity and MK protein expression in affected individuals (PMID: 10369261). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BP4, PM3, PP1, PS3, PS4
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hyper-IgD syndrome (MIM#260920), mevalonic aciduria (MIM#610377) and autosomal dominant porokeratosis 3, multiple types (MIM#175900) (DECIPHER). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported for both conditions. Autosomal dominant porokeratosis 3, multiple types (MIM#175900) may only manifest due to additional circumstances such as environmental factors (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32822427). This gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (221 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common pathogenic variant in the MVK gene and is associated with hyper-IgD syndrome (Infevers database). There are many unrelated patients affected with mevalonate kinase deficiency or hyper-IgD syndrome who were identified as compound heterozygous or homozygous for this variant (ClinVar, PMID: 32822427). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Immunoblot analysis of patient lymphocytes showed minimal MK activity (PMID: 10369261). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The MVK p.Val325Ile variant was identified in 23 of 58 proband chromosomes (frequency: 0.43) from individuals or families with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) (Houten_1999_PMID:10369261; Cuisset_2001_PMID:11313769). The variant was also identified in dbSNP (ID: rs28934897), ClinVar (classified as pathogenic by Invitae, GeneDx and eight other laboratories) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 443 of 280790 chromosomes at a frequency of 0.001578 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 303 of 128360 chromosomes (freq: 0.002361), Latino in 50 of 35436 chromosomes (freq: 0.001411), European (Finnish) in 33 of 23962 chromosomes (freq: 0.001377), Other in 9 of 7198 chromosomes (freq: 0.00125), South Asian in 28 of 30616 chromosomes (freq: 0.000915), Ashkenazi Jewish in 8 of 10360 chromosomes (freq: 0.000772), African in 10 of 24932 chromosomes (freq: 0.000401), and East Asian in 2 of 19926 chromosomes (freq: 0.0001). The V325I variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val325 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However, functional studies expressing cDNA constructs containing the V325I variant in E. coli have demonstrated decreased mevalonate kinase (MK) protein activity compared to wildtype (Houten_1999_PMID:10369261). Decreased MK activity was also found in lymphocytes and fibroblasts from patients with the V325I variant (Houten_1999_PMID:10369261). Interestingly, this variant has been reported in the homozygous state in two sisters, one affected with HIDS and the other who was asymptomatic, therefore suggesting that other genetic factors may influence the presentation of HIDS in individuals with the V325I variant (Messer_2016_PMID:26977311). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The MVK c.1129G>A variant is predicted to result in the amino acid substitution p.Val377Ile. This is a well-documented pathogenic variant for Hyper-IgD syndrome (HIDS) and has been reported in ~90% of the HIDS cases, both in the homozygous and compound heterozygous states (Messer et al. 2016. PubMed ID: 26977311; Schlabe et al. 2016. PubMed ID: 27899390; Houten et al. 2003. PubMed ID: 12634869). Although, there are occasional reports of this variant in patients with mevalonic aciduria (MA) (Favier and Schulert 2016. PubMed ID: 27499643), functional studies did not indicate a profound enzyme deficiency as expected in patients with MA (Cuisset et al. 2001. PubMed ID: 11313769). In addition, this variant is known for its reduced penetrance, leading to a mild or absent phenotype (Houten et al. 2003. PubMed ID: 12634869). This variant is reported in 0.24% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is classified as a pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/11929/). Taken together, this variant is considered a pathogenic variant for HIDS, but its role in mevalonic aciduria is uncertain.
Comment:
Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Two Siblings With Recurrent Fevers: The Path to Mevalonate Kinase Deficiency Diagnosis. | Pereira-Nunes J | Cureus | 2023 | PMID: 36788924 |
| Successful treatment with anakinra in generalized spiculated porokeratosis and severe hidradenitis suppurativa in a patient with MVK and MEFV mutations. | Oktem A | Clinical and experimental dermatology | 2023 | PMID: 36730507 |
| The genomic landscape of rare disorders in the Middle East. | El Naofal M | Genome medicine | 2023 | PMID: 36703223 |
| Ischemic stroke is a potential complication of uncontrolled inflammation in mevalonate kinase deficiency - A case report. | Blais J | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2022 | PMID: 36242899 |
| Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. | Similuk MN | The Journal of allergy and clinical immunology | 2022 | PMID: 35753512 |
| Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa - A New Syndromic Form of HS? A Report of Two Cases. | Guillem P | Frontiers in immunology | 2022 | PMID: 35720358 |
| An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment. | Koç Yekedüz M | Molecular syndromology | 2022 | PMID: 35418827 |
| Homozygous V377I mutation causing mevalonate kinase. | Brito T | BMJ case reports | 2022 | PMID: 35387795 |
| Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report. | Omoyinmi E | Pediatric rheumatology online journal | 2021 | PMID: 34809655 |
| Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. | Grossi A | Genes | 2021 | PMID: 34573280 |
| Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease. | Bader-Meunier B | Inflammatory bowel diseases | 2021 | PMID: 34525209 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets. | Sharma P | Frontiers in genetics | 2021 | PMID: 34054914 |
| Mevalonate Kinase-Associated Diseases: Hunting for Phenotype-Genotype Correlation. | Boursier G | Journal of clinical medicine | 2021 | PMID: 33917151 |
| Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. | Platt CD | The Journal of allergy and clinical immunology | 2021 | PMID: 32888943 |
| Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. | Govindaraj GM | PloS one | 2020 | PMID: 32822427 |
| Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation. | McCreary D | JAMA network open | 2019 | PMID: 31664448 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency. | Munoz MA | Frontiers in immunology | 2019 | PMID: 31474985 |
| Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. | Karacan İ | Rheumatology international | 2019 | PMID: 30783801 |
| Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
| Hyper-IgD syndrome in a patient with IgA immunodeficiency. | Smerla RG | Clinical and experimental rheumatology | 2018 | PMID: 30148429 |
| Multi-OMICS analyses unveil STAT1 as a potential modifier gene in mevalonate kinase deficiency. | Carapito R | Annals of the rheumatic diseases | 2018 | PMID: 30030262 |
| Mevalonate kinase deficiency presenting as recurrent rectal abscesses and perianal fistulae. | Dunn K | Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology | 2018 | PMID: 29290516 |
| Effects of Anakinra on Health-Related Quality of Life in a Patient with 1129G>A/928G>A Mutations in MVK Gene and Heterozygosity for the Mutation 2107C>A in CIAS1 Gene. | Laccetta G | Frontiers in pediatrics | 2017 | PMID: 28638818 |
| Hyperimmunoglobulin D syndrome in an Indian family undiagnosed for 11 years. | Abdulla MC | International journal of rheumatic diseases | 2017 | PMID: 26620804 |
| Hyper-IgD and periodic fever syndrome (HIDS) due to compound heterozygosity for G336S and V377I in a 44-year-old patient with a 27-year history of fever. | Schlabe S | BMJ case reports | 2016 | PMID: 27899390 |
| The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry. | Ter Haar NM | Arthritis & rheumatology (Hoboken, N.J.) | 2016 | PMID: 27213830 |
| Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra. | Peciuliene S | Pediatric rheumatology online journal | 2016 | PMID: 27012807 |
| NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
| Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency. | Durel CA | Medicine | 2016 | PMID: 26986117 |
| Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS). | Messer L | RMD open | 2016 | PMID: 26977311 |
| Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
| Treatment of adult hyper-IgD syndrome with canakinumab. | Curtis CD | The journal of allergy and clinical immunology. In practice | 2015 | PMID: 26116953 |
| Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study. | De Pieri C | Pediatric rheumatology online journal | 2015 | PMID: 25866490 |
| Overlap of familial Mediterranean fever and hyper-IgD syndrome in an Arabic kindred. | Moussa T | Journal of clinical immunology | 2015 | PMID: 25708585 |
| Neonatal hepatitis as first manifestation of hyperimmunoglobulinemia d syndrome. | von Linstow ML | Case reports in pediatrics | 2014 | PMID: 24716072 |
| Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. | Shendi HM | Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases | 2014 | PMID: 24561416 |
| Periodic fever in MVK deficiency: a patient initially diagnosed with incomplete Kawasaki disease. | Thors VS | Pediatrics | 2014 | PMID: 24470648 |
| Clinical and genetic profile of children with periodic fever syndromes from a single medical center in South East Michigan. | Chandrakasan S | Journal of clinical immunology | 2014 | PMID: 24233262 |
| Intermittent neutropenia as an early feature of mild mevalonate kinase deficiency. | Parvaneh N | Journal of clinical immunology | 2014 | PMID: 24177804 |
| Weekly oral alendronate in mevalonate kinase deficiency. | Cantarini L | Orphanet journal of rare diseases | 2013 | PMID: 24360083 |
| Severe early-onset colitis revealing mevalonate kinase deficiency. | Levy M | Pediatrics | 2013 | PMID: 23979089 |
| Mevalonate kinase deficiency (hyper IgD syndrome with periodic fever)--different faces with separate treatments: two cases and review of the literature. | Gençpınar P | The Turkish journal of pediatrics | 2012 | PMID: 23692791 |
| Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children. | Lainka E | Rheumatology international | 2012 | PMID: 22038276 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. | Sornsakrin M | European journal of pediatrics | 2009 | PMID: 18839211 |
| Hyperimmunoglobulinaemia D syndrome in India: report of two siblings with a novel mutation. | Lawrence A | Annals of the rheumatic diseases | 2006 | PMID: 17105862 |
| Identification of a novel mevalonate kinase gene mutation in combination with the common MVK V377I substitution and the low-penetrance TNFRSF1A R92Q mutation. | Hoffmann F | European journal of human genetics : EJHG | 2005 | PMID: 15657603 |
| MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever. | D'Osualdo A | European journal of human genetics : EJHG | 2005 | PMID: 15536479 |
| Confirmation and refinement of a genetic locus for disseminated superficial actinic porokeratosis (DSAP1) at 12q23.2-24.1. | Wu LQ | The British journal of dermatology | 2004 | PMID: 15149516 |
| Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome. | Takada K | Arthritis and rheumatism | 2003 | PMID: 13130485 |
| Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. | Houten SM | European journal of human genetics : EJHG | 2003 | PMID: 12634869 |
| Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. | Houten SM | Human molecular genetics | 2002 | PMID: 12444096 |
| Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. | Cuisset L | European journal of human genetics : EJHG | 2001 | PMID: 11313769 |
| Molecular basis of classical mevalonic aciduria and the hyperimmunoglobulinaemia D and periodic fever syndrome: high frequency of 3 mutations in the mevalonate kinase gene. | Houten SM | Journal of inherited metabolic disease | 2000 | PMID: 10896296 |
| Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. | Drenth JP | Nature genetics | 1999 | PMID: 10369262 |
| Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. | Houten SM | Nature genetics | 1999 | PMID: 10369261 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MVK | - | - | - | - |
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Text-mined citations for rs28934897 ...
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Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.