NM_000431.4(MVK):c.1129G>A (p.Val377Ile) AND Mevalonic aciduria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004783724.2

Allele description [Variation Report for NM_000431.4(MVK):c.1129G>A (p.Val377Ile)]

NM_000431.4(MVK):c.1129G>A (p.Val377Ile)

Gene:

MVK:mevalonate kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_000431.4(MVK):c.1129G>A (p.Val377Ile)

HGVS:

NC_000012.12:g.109596515G>A
NG_007702.1:g.27821G>A
NM_000431.4:c.1129G>AMANE SELECT
NM_001114185.3:c.1129G>A
NM_001301182.2:c.973G>A
NP_000422.1:p.Val377Ile
NP_001107657.1:p.Val377Ile
NP_001288111.1:p.Val325Ile
LRG_156t1:c.1129G>A
LRG_156:g.27821G>A
NC_000012.11:g.110034320G>A
NM_000431.2:c.1129G>A
NM_000431.3:c.1129G>A
NM_000431.4:c.1129G>A
NM_001114185.2:c.1129G>A
NM_001301182.1:c.973G>A
Q03426:p.Val377Ile

Protein change:

V325I; VAL377ILE

Links:

UniProtKB: Q03426#VAR_004027; OMIM: 251170.0002; dbSNP: rs28934897

NCBI 1000 Genomes Browser:

rs28934897

Molecular consequence:

NM_000431.4:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114185.3:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301182.2:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mevalonic aciduria (MEVA)
Identifiers:: MONDO: MONDO:0012481; MedGen: C1959626; Orphanet: 29; OMIM: 610377

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005397680	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2024)	germline	clinical testing	PubMed (26) [See all records that cite these PMIDs] 22038276, 35387795, 26986117, 24177804, 11313769, 34525209, 24233262, 12444096, 10896296, 25866490, 10369262, 27213830, 15536479, 25708585, 23979089, 12634869, 24360083, 17105862, 10369261, 32822427, 24470648, 31474985, 24561416, 33917151, 34809655, 25741868
SCV005399255	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10369261, 32822427, 27012807, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005397680

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2024)

germline

clinical testing

PubMed (26)
[See all records that cite these PMIDs]

SCV005399255

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 31, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children.

Lainka E, Neudorf U, Lohse P, Timmann C, Bielak M, Stojanov S, Huss K, von Kries R, Niehues T.

Rheumatol Int. 2012 Oct;32(10):3253-60. Epub 2011 Oct 30.

PubMed [citation]

PMID:: 22038276

Homozygous V377I mutation causing mevalonate kinase.

Brito T, Banganho D, Pedrosa C, Farela Neves J.

BMJ Case Rep. 2022 Apr 6;15(4). doi: 10.1136/bcr-2022-249135.

PubMed [citation]

PMID:: 35387795
PMCID:: PMC8987701

See all PubMed Citations (27)

Details of each submission

From Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397680.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (26)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399255.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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