Variant summary: GNE c.829C>T (p.Arg277Trp) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251416 control chromosomes. c.829C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Inclusion Body Myopathy/GNE myopathy (example, PMID: 26231298, 21307865, 29305133, 15987957, 20346669). 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 (example, PMID: 15987957). The most pronounced variant effect results in <2% of normal uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE) enzyme activity in-vitro. Five 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.
ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.736C>T (p.Arg246Trp)
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.
(8)
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
8
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.736C>T (p.Arg246Trp)
Variation ID: 197184 Accession: VCV000197184.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.3 9: 36236865 (GRCh38) [ NCBI UCSC ] 9: 36236862 (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 6, 2016 Jun 17, 2024 Jan 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005476.7:c.736C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Arg246Trp missense NM_001128227.3:c.829C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Arg277Trp missense NM_001190383.3:c.736C>T NP_001177312.1:p.Arg246Trp missense NM_001190384.3:c.440-2733C>T intron variant NM_001190388.2:c.559C>T NP_001177317.2:p.Arg187Trp missense NM_001374797.1:c.617-2733C>T intron variant NM_001374798.1:c.559C>T NP_001361727.1:p.Arg187Trp missense NC_000009.12:g.36236865G>A NC_000009.11:g.36236862G>A NG_008246.1:g.45180C>T LRG_1197:g.45180C>T LRG_1197t1:c.829C>T LRG_1197p1:p.Arg277Trp LRG_1197t2:c.736C>T LRG_1197p2:p.Arg246Trp - Protein change
- R277W, R246W, R187W
- Other names
- -
- Canonical SPDI
- NC_000009.12:36236864: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.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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. |
|||
| 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 (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 20, 2023 | RCV000178150.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2024 | RCV000700059.7 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 10, 2023 | RCV000984181.4 |
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
(May 19, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230155.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Dec 24, 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: SCV002819792.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: GNE c.829C>T (p.Arg277Trp) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four … (more)
Variant summary: GNE c.829C>T (p.Arg277Trp) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251416 control chromosomes. c.829C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Inclusion Body Myopathy/GNE myopathy (example, PMID: 26231298, 21307865, 29305133, 15987957, 20346669). 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 (example, PMID: 15987957). The most pronounced variant effect results in <2% of normal uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE) enzyme activity in-vitro. Five 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)
|
|
|
Pathogenic
(Sep 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002513154.3
First in ClinVar: May 21, 2022 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate that this variant leads to significantly reduced enzyme activity (Sparks et al., 2005); Missense variants in this gene are often considered … (more)
Published functional studies demonstrate that this variant leads to significantly reduced enzyme activity (Sparks et al., 2005); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22507750, 12409274, 25966635, 31589614, 30390020, 24796702, 20346669, 19917666, 26231298, 18555875, 25002140, 21307865, 17098358, 15987957, 36360228, 35248449, 35438352, 37066920) (less)
|
|
|
Pathogenic
(Jun 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003824608.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 01, 2024)
|
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: SCV000828798.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 277 of the GNE protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 277 of the GNE protein (p.Arg277Trp). This variant is present in population databases (rs773729410, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive hereditary inclusion body myopathy (PMID: 26231298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197184). 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
(Dec 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005059621.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Sep 26, 2018)
|
no assertion criteria provided
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132210.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Nonaka myopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458438.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
Published functional studies demonstrate that this variant leads to significantly reduced enzyme activity (Sparks et al., 2005); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22507750, 12409274, 25966635, 31589614, 30390020, 24796702, 20346669, 19917666, 26231298, 18555875, 25002140, 21307865, 17098358, 15987957, 36360228, 35248449, 35438352, 37066920)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 277 of the GNE protein (p.Arg277Trp). This variant is present in population databases (rs773729410, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive hereditary inclusion body myopathy (PMID: 26231298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197184). 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.
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:
Variant summary: GNE c.829C>T (p.Arg277Trp) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251416 control chromosomes. c.829C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Inclusion Body Myopathy/GNE myopathy (example, PMID: 26231298, 21307865, 29305133, 15987957, 20346669). 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 (example, PMID: 15987957). The most pronounced variant effect results in <2% of normal uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE) enzyme activity in-vitro. Five 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.
Comment:
Published functional studies demonstrate that this variant leads to significantly reduced enzyme activity (Sparks et al., 2005); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22507750, 12409274, 25966635, 31589614, 30390020, 24796702, 20346669, 19917666, 26231298, 18555875, 25002140, 21307865, 17098358, 15987957, 36360228, 35248449, 35438352, 37066920)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 277 of the GNE protein (p.Arg277Trp). This variant is present in population databases (rs773729410, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive hereditary inclusion body myopathy (PMID: 26231298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197184). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| GNE myopathy in Roma patients homozygous for the p.I618T founder mutation. | Chamova T | Neuromuscular disorders : NMD | 2015 | PMID: 26231298 |
| Mutation update for GNE gene variants associated with GNE myopathy. | Celeste FV | Human mutation | 2014 | PMID: 24796702 |
| Non-specific accumulation of glycosphingolipids in GNE myopathy. | Patzel KA | Journal of inherited metabolic disease | 2014 | PMID: 24136589 |
| 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 |
| Clinical and molecular genetic analysis in Chinese patients with distal myopathy with rimmed vacuoles. | Li H | Journal of human genetics | 2011 | PMID: 21307865 |
| Novel missense mutation p.A310P in the GNE gene in autosomal-recessive hereditary inclusion-body myopathy/distal myopathy with rimmed vacuoles in an Italian family. | Stober A | Neuromuscular disorders : NMD | 2010 | PMID: 20346669 |
| 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 |
| 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 |
| Four novel mutations associated with autosomal recessive inclusion body myopathy (MIM: 600737). | Darvish D | Molecular genetics and metabolism | 2002 | PMID: 12409274 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE | - | - | - | - |
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Text-mined citations for rs773729410 ...
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.