Submissions for variant NM_005476.7(GNE):c.38G>C (p.Cys13Ser)

dbSNP: rs1209266607

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594728	SCV000700792	pathogenic	not provided	2016-11-15	criteria provided, single submitter	clinical testing
Invitae	RCV001853994	SCV002240531	pathogenic	GNE myopathy; Sialuria	2023-04-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127). 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. ClinVar contains an entry for this variant (Variation ID: 496947). This missense change has been observed in individuals with autosomal recessive distal myopathy with rimmed vacuoles (DMRV) (PMID: 14707127, 14733962, 22507750, 27363342, 28403181, 30390020, 31286697). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 44 of the GNE protein (p.Cys44Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000755013	SCV004037813	pathogenic	GNE myopathy	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: GNE c.131G>C (p.Cys44Ser), also referred to as c.89G>C (p.Cys13Ser) in the literature, results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes (gnomAD). c.131G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Inclusion Body Myopathy 2/Distal Myopathy with Rimmed Vacuoles (e.g. Saito_2004, Noguchi_2004, Sim_2013). 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 in vitro and found the UDP-GlcNAc 2-epimerase activity of the variant was approximately 20% of the wild type protein (e.g. Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 14733963, 23549799). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000755013	SCV004199391	pathogenic	GNE myopathy	2023-08-15	criteria provided, single submitter	clinical testing
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000755013	SCV000882745	pathogenic	GNE myopathy	2019-02-11	no assertion criteria provided	research
Counsyl	RCV000755013	SCV001132211	pathogenic	GNE myopathy	2019-06-27	no assertion criteria provided	clinical testing
GeneReviews	RCV000755013	SCV001364089	not provided	GNE myopathy		no assertion provided	literature only