ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.2135T>C (p.Met712Thr) (rs28937594)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000006396 SCV000485129 pathogenic GNE myopathy 2015-12-18 criteria provided, single submitter clinical testing
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000443895 SCV000331555 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing
FirmaLab RCV000006396 SCV000106038 pathogenic GNE myopathy no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763615 SCV000894469 pathogenic GNE myopathy; Sialuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000443895 SCV000513166 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing The M743T variant in the GNE gene has been reported previously in the homozygous and compound heterozygousstate in multiple unrelated individuals with GNE-related myopathy (Eisenberg et al., 2001; Haghighi et al., 2016;Broccolini et al., 2002). The M743T variant is a founder variant that is common in the Persian Jewish population(Eisenberg et al., 2001). Functional studies demonstrate that the M743T variant results in reduced activity comparedto wild-type, presumably due to the introduction of an additional phosphorylation/O-GlcNAcylation site as theM743T variant shows increased O-GlcNAcylation as compared to wild-type (Bennmann et al., 2016). The M743Tvariant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The M743T variant isa non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties and occurs at a position where amino acids with similarproperties to Methionine are tolerated across species. We interpret M743T as a pathogenic variant.
GeneReviews RCV000006396 SCV000058062 pathologic GNE myopathy 2013-03-07 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000763615 SCV000823050 pathogenic GNE myopathy; Sialuria 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 743 of the GNE protein (p.Met743Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs28937594, ExAC 0.006%). This variant has been reported as homozygous and in combination with another GNE variant in several individuals affected with inclusion body myopathy and segregated with disease in an affected family (PMID: 11528398, 20300792, 23278550). This variant is considered a founder variant in the Persian Jewish population (PMID: 11528398, 23278550). This variant is also known as c.2186T>C (p.Met712Thr) in the literature. ClinVar contains an entry for this variant (Variation ID: 6025). Experimental studies have shown that this missense change reduces the epimerase activity of the GNE enzyme (PMID: 15670773, 15147877). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006396 SCV000026578 pathogenic GNE myopathy 2004-05-11 no assertion criteria provided literature only
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

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