Submissions for variant NM_005476.7(GNE):c.2135T>C (p.Met712Thr)

gnomAD frequency: 0.00001  dbSNP: rs28937594

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000443895	SCV000331555	pathogenic	not provided	2017-04-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000443895	SCV000513166	pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced activity compared to wild-type, presumably due to the introduction of an additional phosphorylation/O-GlcNAcylation site as the M743T variant shows increased O-GlcNAcylation as compared to wild-type (Bennmann et al., 2016); The majority of missense variants in this gene are considered pathogenic (HGMD); A founder variant common in the Persian Jewish population (Eisenberg et al., 2001); This variant is associated with the following publications: (PMID: 24136589, 22975760, 20300792, 27023225, 23278550, 17673919, 22322304, 15670773, 15147877, 19917666, 22507750, 21873062, 23238814, 27037841, 15987957, 11528398, 25966635, 12473780, 27671536, 24264357, 28267778, 15136692, 34426522, 31589614, 19787087)
Invitae	RCV000763615	SCV000823050	pathogenic	GNE myopathy; Sialuria	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 743 of the GNE protein (p.Met743Thr). This variant is present in population databases (rs28937594, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy (PMID: 11528398, 20300792, 23278550). It is commonly reported in individuals of Persian ancestry (PMID: 11528398, 20300792, 23278550). This variant is also known as c.2186T>C (p.Met712Thr). ClinVar contains an entry for this variant (Variation ID: 6025). 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: 15147877, 15670773). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763615	SCV000894469	pathogenic	GNE myopathy; Sialuria	2021-07-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763615	SCV001163609	pathogenic	GNE myopathy; Sialuria		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000006396	SCV001194231	pathogenic	GNE myopathy	2019-12-20	criteria provided, single submitter	clinical testing	NM_005476.5(GNE):c.2135T>C(M712T) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 21873062, 11528398, 12497639, 20300792 and 15987957. Classification of NM_005476.5(GNE):c.2135T>C(M712T) 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.‚Äã
Mayo Clinic Laboratories, Mayo Clinic	RCV000443895	SCV001714897	pathogenic	not provided	2019-12-09	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PM3, PP5
Genome-Nilou Lab	RCV001705582	SCV001810459	pathogenic	Sialuria	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000443895	SCV002024879	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing
3billion	RCV000006396	SCV002318651	pathogenic	GNE myopathy	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006025, PMID:11528398). The variant was co-segregated with Nonaka myopathy in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 11528398). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 15670773, 15147877). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.756>=0.6, 3CNET: 0.836>=0.75). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000398). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Hadassah Hebrew University Medical Center	RCV000006396	SCV004099503	pathogenic	GNE myopathy		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006396	SCV004199375	pathogenic	GNE myopathy	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000006396	SCV000026578	pathogenic	GNE myopathy	2004-05-11	no assertion criteria provided	literature only
GeneReviews	RCV000006396	SCV000058062	not provided	GNE myopathy		no assertion provided	literature only
FirmaLab, FirmaLab	RCV000006396	SCV000106038	pathogenic	GNE myopathy		no assertion criteria provided	clinical testing
Sema4, Sema4	RCV000006396	SCV000196518	pathogenic	GNE myopathy	2014-11-01	no assertion criteria provided	clinical testing	8 patients from 7 non-Jewish Persian families were homozygous for this variant
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000006396	SCV000882763	pathogenic	GNE myopathy	2019-02-11	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000006396	SCV001190834	pathogenic	GNE myopathy	2020-02-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000006396	SCV001458426	pathogenic	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing