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

gnomAD frequency: 0.00001  dbSNP: rs28937594

Total submissions: 22

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)
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006396	SCV004813788	pathogenic	GNE myopathy	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: GNE c.2228T>C (p.Met743Thr) also known as p.Met712Thr, results in a non-conservative amino acid change in the encoded protein sequence. Four 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-05 in 251286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.2228T>C has been reported as the common Persian Jewish mutation in the literature in multiple individuals affected with Inclusion Body Myopathy 2 from Middle East (example, Argov_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impared GNE function and accumulated Glycosphingolipid levels in both primary fibroblasts from patients and knock-in mice with homozygous p.Met743Thr (Patzel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 12743242, 24136589). ClinVar contains an entry for this variant (Variation ID: 6025). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000006396	SCV004848011	pathogenic	GNE myopathy	2022-11-05	criteria provided, single submitter	clinical testing	The p.Met743Thr variant in GNE (also reported in literature as Met712Thr) has been reported in >50 individuals with inclusion body myopathy in the homozygous and compound heterozygous state and segregated with disease in >50 affected individuals from multiple families (Eisenberg 2001 PMID: 11528398, Broccolini 2002 PMID: 12473780, Grandis 2010 PMID: 20300792, Khademian 2013 PMID: 23278550). It has been found in the homozygous state in some apparently asymptomatic family members which could give some evidence to reduced penetrance (Argov 2003 PMID: 1274324). It has also been identified in 0.001% (1/68034) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 6025). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support some impact on protein function, including increased glycosphingolipids in cells (Salama 2005 PMID: 15670773, Sparks 2005 PMID: 15987957, Patzel 2013 PMID: 24136589). Mouse models homozygous for the Met743Thr variant showed >90% lethality, severe hematuria, proteinuria and glomerulopathy, though in a later study variable phenotypes of mice were found (Kakani 2012 PMID: 22322304, Sela 2013 PMID: 23238814, Patzel 2013 PMID: 24136589). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GNE myopathy. ACMG/AMP Criteria applied: PP1_Strong, PM3, PS3_Moderate, PM2_Supporting, PP3.
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
PreventionGenetics, part of Exact Sciences	RCV004748503	SCV005360219	pathogenic	GNE-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The GNE c.2228T>C variant is predicted to result in the amino acid substitution p.Met743Thr. This variant is also known as (g.36217396A>G, c.2135T>C, p.Met712Thr with alternative transcript NM_005476.5). This variant has been reported as a pathogenic founder variant in certain populations (Persian-Jewish) and is well documented to be causative for GNE myopathy (Eisenberg et al. 2001. PubMed ID: 11528398; Mori-Yoshimura et al. 2012. PubMed ID: 22507750; Haghighi et al. 2016. PubMed ID: 25966635). Enzymatic studies and mouse models with the c.2228T>C variant support the pathogenicity of this variant (Sparks et al. 2005. PubMed ID: 15987957; Patzel et al. 2014. PubMed ID: 24136589). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic in ClinVar by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6025/). This variant is interpreted as pathogenic for recessive GNE myopathy.