Submissions for variant NM_005476.7(GNE):c.1760T>C (p.Ile587Thr)

gnomAD frequency: 0.00002  dbSNP: rs748949603

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591867	SCV000701266	pathogenic	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003518	SCV000894472	pathogenic	GNE myopathy; Sialuria; Thrombocytopenia 12 with or without myopathy	2024-05-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763618	SCV001209855	pathogenic	GNE myopathy; Sialuria	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the GNE protein (p.Ile618Thr). This variant is present in population databases (rs748949603, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive myopathy (PMID: 12497639, 24695763, 26231298). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1811T>C (Ile587Thr). ClinVar contains an entry for this variant (Variation ID: 188882). 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. Experimental studies have shown that this missense change affects GNE function (PMID: 16503651). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000591867	SCV001248055	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	GNE: PM3:Strong, PM1, PM2, PP4:Moderate, PP2
Revvity Omics, Revvity	RCV000591867	SCV002024881	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000366480	SCV002511602	pathogenic	GNE myopathy	2022-04-24	criteria provided, single submitter	clinical testing	Variant summary: GNE c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ATPase, nucleotide binding domain (IPR043129) of 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 4e-06 in 251492 control chromosomes. c.1853T>C has been reported in the literature as a founder mutation of Roma origin in homozygous and compound heterozygous genotypes among individuals affected with Inclusion Body Myopathy 2 (example, Tasca_2012, Chaouch_2014, Chamova_2015). 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. Eight 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion, Medical Genetics	RCV000366480	SCV003842032	pathogenic	GNE myopathy	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188882). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 12497639, 26231298). A different missense change at the same codon (p.Ile587Asn) has been reported to be associated with GNE related disorder (PMID: 24027297). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM	RCV000366480	SCV004048194	pathogenic	GNE myopathy	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.1760T>C(p.Ile587Thr) variant in GNE gene has been reported previously in homozygous state in individual(s) affected with GNE myopathy (Chamova et al., 2015). Experimental studies have shown that this missense change affects GNE function (Penner et al., 2006). This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Ile at position 587 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile587Thr in GNE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Damaging, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000366480	SCV005059606	pathogenic	GNE myopathy	2024-03-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000591867	SCV005325858	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant results in impaired protein function (PMID: 16503651); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24796702, 31561939, 19917666, 22231866, 27854221, 29431110, 32403337, 33250842, 33197058, 35138478, 35723113, 26231298, 24695763, 26627873, 16503651, 29480215, 35503500, 12497639, 35398442)
Counsyl	RCV000366480	SCV000220508	pathogenic	GNE myopathy	2018-12-03	no assertion criteria provided	clinical testing
GeneReviews	RCV000366480	SCV001364093	not provided	GNE myopathy		no assertion provided	literature only
Natera, Inc.	RCV000366480	SCV001458433	pathogenic	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing