Submissions for variant NM_005476.7(GNE):c.829C>T (p.Arg277Cys)

gnomAD frequency: 0.00002  dbSNP: rs762106720

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726859	SCV000703666	pathogenic	not provided	2016-12-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041020	SCV001204614	pathogenic	GNE myopathy; Sialuria	2024-04-07	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000169197	SCV002060388	likely pathogenic	GNE myopathy	2021-11-03	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000726859	SCV003824653	pathogenic	not provided	2022-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169197	SCV004038920	pathogenic	GNE myopathy	2023-08-10	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000169197	SCV004199385	pathogenic	GNE myopathy	2024-02-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000169197	SCV005042950	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing	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.
Natera, Inc.	RCV000169197	SCV002075658	pathogenic	GNE myopathy	2020-07-17	no assertion criteria provided	clinical testing