Submissions for variant NM_005476.7(GNE):c.2005G>A (p.Gly669Arg)

gnomAD frequency: 0.00002  dbSNP: rs776384541

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535604	SCV000632649	pathogenic	GNE myopathy; Sialuria	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 700 of the GNE protein (p.Gly700Arg). This variant is present in population databases (rs776384541, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive distal myopathy (PMID: 23437777, 24027297, 29480215; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly669Arg. ClinVar contains an entry for this variant (Variation ID: 290224). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000593273	SCV000701430	uncertain significance	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114458	SCV003800858	uncertain significance	not specified	2023-01-17	criteria provided, single submitter	clinical testing	Variant summary: GNE c.2098G>A (p.Gly700Arg) results in a non-conservative amino acid change located in the ATPase, nucleotide binding domain (IPR043129) of the encoded protein sequence. Five 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 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2098G>A has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual with features of Hereditary Inclusion Body Myopathy (example, No_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV001274362	SCV003802754	likely pathogenic	GNE myopathy	2023-02-02	criteria provided, single submitter	clinical testing	The c.2005G>A variant is not present in publicly available population databases like 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. The variant is present in ExAC and gnomAD at low frequencies. This variant has been previously observed in affected individuals, published in literature [PMID:23437777; PMID:27858732; PMID:19917666; PMID:29941673] and reported to HGMD (ID: CM134919). It has been reported to the ClinVar database (Accession ID: VCV000290224.7) as ‘Uncertain significance’ by multiple submitters. In silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome etc predicted this variant to be likely deleterious. The variant is located in a mutational hotspot region of the gene. This individual harbours another heterozygous variant (c.1609T>C) in GNE gene.
Revvity Omics, Revvity	RCV000593273	SCV003815072	uncertain significance	not provided	2022-06-25	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001274362	SCV005439082	pathogenic	GNE myopathy	2023-06-22	criteria provided, single submitter	clinical testing	The missense variant c.2005G>A p.Gly669Arg in the GNE gene has been reported previously in homozygous state in individuals affected with hereditary inclusion body myopathy HIBM or sialuria and congenital thrombocytopenia Futterer et al., 2018; Kurochkina et al., 2010. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/ Likely pathogenic/ Uncertain significance. However, functional evidence on its pathogenicity is not available. The amino acid Gly at position 669 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on the GNE gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005044551	SCV005682205	likely pathogenic	GNE myopathy; Sialuria; Thrombocytopenia 12 with or without myopathy	2024-03-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274362	SCV001458428	uncertain significance	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing