rs773729410
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_Very_Strong
The NM_001128227.3(GNE):c.829C>T(p.Arg277Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001128227.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.829C>T | p.Arg277Trp | missense_variant | 4/12 | ENST00000396594.8 | |
GNE | NM_005476.7 | c.736C>T | p.Arg246Trp | missense_variant | 4/12 | ENST00000642385.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.829C>T | p.Arg277Trp | missense_variant | 4/12 | 1 | NM_001128227.3 | ||
GNE | ENST00000642385.2 | c.736C>T | p.Arg246Trp | missense_variant | 4/12 | NM_005476.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251416Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135882
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461292Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727002
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 26, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 24, 2022 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 10, 2023 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | 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) - |
Sialuria;C1853926:GNE myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at