Submissions for variant NM_005476.7(GNE):c.1892C>T (p.Ala631Val)

gnomAD frequency: 0.00011  dbSNP: rs62541771

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254883	SCV000321742	pathogenic	not provided	2024-06-21	criteria provided, single submitter	clinical testing	Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127)
Eurofins Ntd Llc (ga)	RCV000254883	SCV000331895	pathogenic	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000006406	SCV000538036	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing	The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy.
Athena Diagnostics	RCV000254883	SCV000613535	pathogenic	not provided	2017-01-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763617	SCV000638331	pathogenic	GNE myopathy; Sialuria	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763617	SCV000894471	pathogenic	GNE myopathy; Sialuria	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763617	SCV001163611	pathogenic	GNE myopathy; Sialuria		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000006406	SCV001194129	pathogenic	GNE myopathy	2019-12-20	criteria provided, single submitter	clinical testing	NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000254883	SCV001248054	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000006406	SCV001251481	pathogenic	GNE myopathy		criteria provided, single submitter	research	The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763).
Baylor Genetics	RCV000006406	SCV001527752	pathogenic	GNE myopathy	2024-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000254883	SCV002024869	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000006406	SCV002059317	pathogenic	GNE myopathy	2019-12-03	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000006406	SCV002577401	pathogenic	GNE myopathy	2022-07-14	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
Mayo Clinic Laboratories, Mayo Clinic	RCV000254883	SCV004226607	pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_strong, PS3, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525844	SCV005039440	pathogenic	Hereditary nonpolyposis colon cancer	2024-03-12	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566685	SCV005051801	pathogenic	Thrombocytopenia 12 with or without myopathy	2024-02-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006406	SCV005062084	pathogenic	GNE myopathy	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in 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 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000006406	SCV000026589	pathogenic	GNE myopathy	2002-12-10	no assertion criteria provided	literature only
GeneReviews	RCV000006406	SCV001364094	not provided	GNE myopathy		no assertion provided	literature only
Natera, Inc.	RCV000006406	SCV001458429	pathogenic	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing