Functional studies have shown that the V216A variant reduces GNE enzyme activity (Sparks et al., 2005).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24695763, 19917666, 33214394, 30564623, 15987957, 14972325, 25002140, 12473769)
ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.647T>C (p.Val216Ala)
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.
(12)
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005476.7(GNE):c.647T>C (p.Val216Ala)
Variation ID: 218297 Accession: VCV000218297.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.3 9: 36236954 (GRCh38) [ NCBI UCSC ] 9: 36236951 (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 Dec 13, 2015 Jun 17, 2024 Jan 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005476.7:c.647T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Val216Ala missense NM_001128227.3:c.740T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Val247Ala missense NM_001190383.3:c.647T>C NP_001177312.1:p.Val216Ala missense NM_001190384.3:c.440-2822T>C intron variant NM_001190388.2:c.470T>C NP_001177317.2:p.Val157Ala missense NM_001374797.1:c.617-2822T>C intron variant NM_001374798.1:c.470T>C NP_001361727.1:p.Val157Ala missense NC_000009.12:g.36236954A>G NC_000009.11:g.36236951A>G NG_008246.1:g.45091T>C LRG_1197:g.45091T>C LRG_1197t1:c.740T>C LRG_1197p1:p.Val247Ala LRG_1197t2:c.647T>C LRG_1197p2:p.Val216Ala - Protein change
- V216A, V247A, V157A
- Other names
- -
- Canonical SPDI
- NC_000009.12:36236953:A:G
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
- Comment on variant
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. |
|||
| GNE | - | - |
GRCh38 GRCh37 |
1053 | 1131 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000202427.9 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 25, 2022 | RCV000255797.12 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 16, 2023 | RCV000627756.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613536.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Likely pathogenic
(Mar 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339268.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321741.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional studies have shown that the V216A variant reduces GNE enzyme activity (Sparks et al., 2005).; In silico analysis supports that this missense variant has … (more)
Functional studies have shown that the V216A variant reduces GNE enzyme activity (Sparks et al., 2005).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24695763, 19917666, 33214394, 30564623, 15987957, 14972325, 25002140, 12473769) (less)
|
|
|
Pathogenic
(Nov 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Sialuria
GNE myopathy
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: SCV000638336.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 247 of the GNE protein (p.Val247Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 247 of the GNE protein (p.Val247Ala). This variant is present in population databases (rs779694939, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myopathy (PMID: 12473769, 24136589, 24695763). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val216Ala. ClinVar contains an entry for this variant (Variation ID: 218297). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 15987957). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000789772.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
GNE myopathy Sialuria
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163613.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Pathogenic
(Aug 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572205.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: GNE c.740T>C (p.Val247Ala) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five … (more)
Variant summary: GNE c.740T>C (p.Val247Ala) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.740T>C has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (example, Vasconcelos_2002, Gottileb_2005, Chaouch_2014, Patzel_2014, Chrisman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sparks_2005). The most pronounced variant effect results in <2% of normal epimerase activity in-vitro. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Nov 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Sialuria
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002791544.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Jun 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003828614.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199383.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 10, 2002)
|
no assertion criteria provided
Method: literature only
|
NONAKA MYOPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000257487.1
First in ClinVar: Dec 13, 2015 Last updated: Dec 13, 2015 |
Comment on evidence:
For discussion of the 698T-C transition in the GNE gene, resulting in a val216-to-ala (V216A) substitution, that was found in compound heterozygous state in affected … (more)
For discussion of the 698T-C transition in the GNE gene, resulting in a val216-to-ala (V216A) substitution, that was found in compound heterozygous state in affected members of an American family with Nonaka myopathy (NM; 605820) by Vasconcelos et al. (2002), see 603824.0015. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Nonaka myopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458440.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 247 of the GNE protein (p.Val247Ala). This variant is present in population databases (rs779694939, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myopathy (PMID: 12473769, 24136589, 24695763). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val216Ala. ClinVar contains an entry for this variant (Variation ID: 218297). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 15987957). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: GNE c.740T>C (p.Val247Ala) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.740T>C has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (example, Vasconcelos_2002, Gottileb_2005, Chaouch_2014, Patzel_2014, Chrisman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sparks_2005). The most pronounced variant effect results in <2% of normal epimerase activity in-vitro. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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:
Functional studies have shown that the V216A variant reduces GNE enzyme activity (Sparks et al., 2005).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24695763, 19917666, 33214394, 30564623, 15987957, 14972325, 25002140, 12473769)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 247 of the GNE protein (p.Val247Ala). This variant is present in population databases (rs779694939, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myopathy (PMID: 12473769, 24136589, 24695763). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val216Ala. ClinVar contains an entry for this variant (Variation ID: 218297). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 15987957). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: GNE c.740T>C (p.Val247Ala) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251348 control chromosomes. c.740T>C has been reported in the literature in individuals affected with Inclusion Body Myopathy 2 (example, Vasconcelos_2002, Gottileb_2005, Chaouch_2014, Patzel_2014, Chrisman_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sparks_2005). The most pronounced variant effect results in <2% of normal epimerase activity in-vitro. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GNE Myopathy as a Myofibrillar Myopathy: Potential Important Disease Mechanism Implied by Muscle Biopsy. | Chrisman C | Journal of clinical neuromuscular disease | 2020 | PMID: 33214394 |
| Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: First report from the GNE myopathy Disease Monitoring Program, registry portion. | Pogoryelova O | Neuromuscular disorders : NMD | 2018 | PMID: 29305133 |
| Sialylation of Thomsen-Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy. | Leoyklang P | Biomarkers in medicine | 2014 | PMID: 25123033 |
| Two recurrent mutations are associated with GNE myopathy in the North of Britain. | Chaouch A | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24695763 |
| Non-specific accumulation of glycosphingolipids in GNE myopathy. | Patzel KA | Journal of inherited metabolic disease | 2014 | PMID: 24136589 |
| Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria. | Kurochkina N | Glycobiology | 2010 | PMID: 19917666 |
| Single nucleotide polymorphisms in the dystroglycan gene do not correlate with disease severity in hereditary inclusion body myopathy. | Gottlieb E | Molecular genetics and metabolism | 2005 | PMID: 16112887 |
| Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human hereditary inclusion body myopathy. | Sparks SE | Glycobiology | 2005 | PMID: 15987957 |
| Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. | Huizing M | Molecular genetics and metabolism | 2004 | PMID: 14972325 |
| GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. | Vasconcelos OM | Neurology | 2002 | PMID: 12473769 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs779694939 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
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.
NCBI staff reviewed the sequence information reported in PubMed 12473769 Fig. 2d to determine the location of this allele on the current reference sequence.