Submissions for variant NM_005476.7(GNE):c.737G>A (p.Arg246Gln)

gnomAD frequency: 0.00003  dbSNP: rs121908629

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000202425	SCV000485514	likely pathogenic	GNE myopathy	2015-12-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725734	SCV000701108	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051696	SCV001215864	pathogenic	GNE myopathy; Sialuria	2025-01-26	criteria provided, single submitter	clinical testing	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). Invitae Evidence 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 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.
GeneDx	RCV000725734	SCV001766481	pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000725734	SCV002018490	likely pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000202425	SCV002580635	pathogenic	GNE myopathy	2022-01-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003339	SCV002803000	pathogenic	GNE myopathy; Sialuria; Thrombocytopenia 12 with or without myopathy	2024-04-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725734	SCV002821943	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	GNE: PM3:Very Strong, PM2, PM5, PP1, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202425	SCV004803874	pathogenic	GNE myopathy	2024-01-19	criteria provided, single submitter	clinical testing	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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004585989	SCV005038560	likely pathogenic	Myopathy, autophagic vacuolar, infantile-onset	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PM5+PP2+PP3+PP4+PP5
OMIM	RCV000202425	SCV000026584	pathogenic	GNE myopathy	2001-09-01	no assertion criteria provided	literature only
Sema4, Sema4	RCV000202425	SCV000196517	pathogenic	GNE myopathy	2014-11-01	no assertion criteria provided	clinical testing	4 patients from two non-Jewish Persian families were homozygous for this variant
GeneReviews	RCV000202425	SCV001364090	not provided	GNE myopathy		no assertion provided	literature only
Natera, Inc.	RCV000202425	SCV001458437	pathogenic	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing