Submissions for variant NM_005476.7(GNE):c.2023T>C (p.Tyr675His)

gnomAD frequency: 0.00001  dbSNP: rs1191857860

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067578	SCV001232646	pathogenic	GNE myopathy; Sialuria	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 706 of the GNE protein (p.Tyr706His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with inclusion body myopathy (PMID: 12409274, 20059379, 29406958). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Y675H. ClinVar contains an entry for this variant (Variation ID: 861130). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509608	SCV002819849	pathogenic	GNE myopathy	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: GNE c.2116T>C (p.Tyr706His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. c.2116T>C has been reported in the literature in multiple individuals affected with Inclusion Body Myopathy 2 or related disorders. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV003142021	SCV003824630	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002509608	SCV004013986	pathogenic	GNE myopathy	2022-12-19	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
Baylor Genetics	RCV002509608	SCV004191657	pathogenic	GNE myopathy	2024-03-27	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004587035	SCV005038559	likely pathogenic	Myopathy, autophagic vacuolar, infantile-onset	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PP2+PP3+PP4+PP5