ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.1798G>A (p.Ala600Thr)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005476.7(GNE):c.1798G>A (p.Ala600Thr)
Variation ID: 286014 Accession: VCV000286014.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 36219856 (GRCh38) [ NCBI UCSC ] 9: 36219853 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 2, 2017 Jun 17, 2024 Mar 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005476.7:c.1798G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Ala600Thr missense NM_001128227.3:c.1891G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Ala631Thr missense NM_001190383.3:c.1576G>A NP_001177312.1:p.Ala526Thr missense NM_001190384.3:c.1468G>A NP_001177313.1:p.Ala490Thr missense NM_001190388.2:c.1621G>A NP_001177317.2:p.Ala541Thr missense NM_001374797.1:c.1645G>A NP_001361726.1:p.Ala549Thr missense NM_001374798.1:c.1621G>A NP_001361727.1:p.Ala541Thr missense NC_000009.12:g.36219856C>T NC_000009.11:g.36219853C>T NG_008246.1:g.62189G>A LRG_1197:g.62189G>A LRG_1197t1:c.1891G>A LRG_1197p1:p.Ala631Thr LRG_1197t2:c.1798G>A LRG_1197p2:p.Ala600Thr - Protein change
- A631T, A600T, A526T, A490T, A541T, A549T
- Other names
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- Canonical SPDI
- NC_000009.12:36219855:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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GNE | - | - |
GRCh38 GRCh37 |
1048 | 1126 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Feb 3, 2023 | RCV000494055.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2023 | RCV001385137.7 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 19, 2024 | RCV000675176.5 |
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
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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
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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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Likely pathogenic
(Feb 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000582972.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as A600T using alternate nomenclature; This variant is associated with the following publications: (PMID: 19917666, 24796702, 19596068, 15146476) (less)
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Likely pathogenic
(Feb 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800804.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Apr 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001584893.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 286014). This variant is also known as p.A600T. This missense change has been observed in individuals … (more)
ClinVar contains an entry for this variant (Variation ID: 286014). This variant is also known as p.A600T. This missense change has been observed in individuals with hereditary inclusion body myopathy and distal myopathy (PMID: 11528398, 15146476, 18555875). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the GNE protein (p.Ala631Thr). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala631 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12497639, 22507750, 24027297). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNE function (PMID: 16503651). 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. (less)
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Likely pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803576.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: GNE c.1891G>A (p.Ala631Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GNE c.1891G>A (p.Ala631Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). c.1891G>A has been reported in the literature in individuals affected with hereditary inclusion-body myopathy (examples: Broccolini_2004, Huizing_2003, and Eisenberg_2001). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Penner_2006). A different variant (c.1892C>T/p.Ala631Val) affecting this residue has been classified pathogenic in ClinVar (CV ID 6035). The following publications have been ascertained in the context of this evaluation (PMID: 15146476, 11528398, 19596068, 16503651). ClinVar contains an entry for this variant (Variation ID: 286014). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191647.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Nonaka myopathy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458431.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(Mar 16, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000339267.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy). | Cho A | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24027297 |
Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. | Mori-Yoshimura M | Journal of the neurological sciences | 2012 | PMID: 22507750 |
Hereditary inclusion body myopathy: a decade of progress. | Huizing M | Biochimica et biophysica acta | 2009 | PMID: 19596068 |
[Distal myopathy due to mutations of GNE gene: clinical spectrum and diagnosis]. | Béhin A | Revue neurologique | 2008 | PMID: 18555875 |
Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy. | Penner J | Biochemistry | 2006 | PMID: 16503651 |
Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy. | Broccolini A | Human mutation | 2004 | PMID: 15146476 |
Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. | Eisenberg I | Human mutation | 2003 | PMID: 12497639 |
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. | Eisenberg I | Nature genetics | 2001 | PMID: 11528398 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE | - | - | - | - |
Text-mined citations for rs387906347 ...
HelpRecord 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.