9-36236864-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP2PP5_Very_StrongBP4
The NM_001128227.3(GNE):c.830G>A(p.Arg277Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R277W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001128227.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNE | NM_001128227.3 | c.830G>A | p.Arg277Gln | missense_variant | 4/12 | ENST00000396594.8 | |
GNE | NM_005476.7 | c.737G>A | p.Arg246Gln | missense_variant | 4/12 | ENST00000642385.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNE | ENST00000396594.8 | c.830G>A | p.Arg277Gln | missense_variant | 4/12 | 1 | NM_001128227.3 | ||
GNE | ENST00000642385.2 | c.737G>A | p.Arg246Gln | missense_variant | 4/12 | NM_005476.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251416Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135882
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461480Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46AN XY: 727072
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
GNE myopathy Pathogenic:6Other:1
Pathogenic, no assertion criteria provided | clinical testing | Sema4, Sema4 | Nov 01, 2014 | 4 patients from two non-Jewish Persian families were homozygous for this variant - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2001 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2024 | Variant summary: GNE c.830G>A (p.Arg277Gln) results in a conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251416 control chromosomes (gnomAD). c.830G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Inclusion Body Myopathy 2 (e.g. Lv_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35138478). ClinVar contains an entry for this variant (Variation ID: 6030). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 18, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 29, 2015 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | GNE: PM3:Very Strong, PM2, PM5, PP1, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2023 | 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 R246Q using alternate nomenclature; This variant is associated with the following publications: (PMID: 19917666, 24027297, 25966635, 15146476, 24695763, 11528398, 29406958, 20301439, 31589614, 24796702, 33250842, 33214394, 22231866, 34676965, 30390020) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 11, 2020 | - - |
Sialuria;C1853926:GNE myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 277 of the GNE protein (p.Arg277Gln). This variant is present in population databases (rs121908629, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive distal myopathy (PMID: 24695763, 29406958, 29480215). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R246Q. ClinVar contains an entry for this variant (Variation ID: 6030). 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.Arg277 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15987957, 22507750, 26231298). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 15, 2021 | - - |
Myopathy, autophagic vacuolar, infantile-onset Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PM1+PM2+PM5+PP2+PP3+PP4+PP5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at