rs786204511
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong
The NM_001128227.3(GNE):c.922C>T(p.Arg308Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,780 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. R308G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001128227.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.922C>T | p.Arg308Cys | missense_variant | 5/12 | ENST00000396594.8 | |
GNE | NM_005476.7 | c.829C>T | p.Arg277Cys | missense_variant | 5/12 | ENST00000642385.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.922C>T | p.Arg308Cys | missense_variant | 5/12 | 1 | NM_001128227.3 | ||
GNE | ENST00000642385.2 | c.829C>T | p.Arg277Cys | missense_variant | 5/12 | NM_005476.7 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251480Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461780Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727214
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 17, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_001128227.2(GNE):c.922C>T(R308C) is a missense variant classified as likely pathogenic in the context of GNE myopathy. R308C has been observed in cases with relevant disease (PMID: 24027297, 24695763, 22231866, 27858732, 29997562, 29480215). Functional assessments of this variant are not available in the literature. R308C has been observed in population frequency databases (gnomAD: EAS 0.01%). NM_001128227.2(GNE):c.922C>T(R308C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: GNE c.922C>T (p.Arg308Cys) 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 2e-05 in 251480 control chromosomes. c.922C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with GNE/Inclusion Body Myopathy 2 (example, Mori-Yoshimura_2012, Cerino_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27858732, 24695763, 22507750, 22231866). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.829C>Tp.Arg277Cys in GNE gene has been reported previously in homozygous and compoundheterozygous state in multiple individuals with GNE Myopathy Bugiardini E, et al., 2018, Chaouch A, et al., 2014. The variant has0.002% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant disrupts thep.Arg308 amino acid residue in GNE. Other variants that disrupt this residue have been observed in individuals with GNE-relatedconditions Cho A, et al., 2014. It has also been observed to segregate with disease in related individuals. This variant has beenreported to the ClinVar database as Pathogenic/Likely Pathogenic.The amino acid Arginine at position 277 is changed to aCysteine changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid changep.Arg277Cys in GNE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant hasbeen classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 25, 2022 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 308 of the GNE protein (p.Arg308Cys). This variant is present in population databases (rs762106720, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 18555875, 22507750, 24027297, 24695763, 29480215). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg277Cys. ClinVar contains an entry for this variant (Variation ID: 188847). 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. This variant disrupts the p.Arg308 amino acid residue in GNE. Other variant(s) that disrupt this residue have been observed in individuals with GNE-related conditions (PMID: 24027297), which suggests that this may be a clinically significant amino acid residue. 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