ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.1798G>A (p.Ala600Thr)

dbSNP: rs387906347
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494055 SCV000582972 likely pathogenic not provided 2023-02-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as A600T using alternate nomenclature; This variant is associated with the following publications: (PMID: 19917666, 24796702, 19596068, 15146476)
Counsyl RCV000675176 SCV000800804 likely pathogenic GNE myopathy 2018-02-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001385137 SCV001584893 pathogenic GNE myopathy; Sialuria 2023-04-26 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala631 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12497639, 22507750, 24027297). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNE function (PMID: 16503651). 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. ClinVar contains an entry for this variant (Variation ID: 286014). This variant is also known as p.A600T. This missense change has been observed in individuals with hereditary inclusion body myopathy and distal myopathy (PMID: 11528398, 15146476, 18555875). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the GNE protein (p.Ala631Thr).
Baylor Genetics RCV000675176 SCV004191647 pathogenic GNE myopathy 2024-03-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000675176 SCV004803576 likely pathogenic GNE myopathy 2024-01-22 criteria provided, single submitter clinical testing Variant summary: GNE c.1891G>A (p.Ala631Thr) 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 was absent in 251472 control chromosomes (gnomAD). c.1891G>A has been reported in the literature in individuals affected with hereditary inclusion-body myopathy (examples: Broccolini_2004, Huizing_2003, and Eisenberg_2001). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Penner_2006). A different variant (c.1892C>T/p.Ala631Val) affecting this residue has been classified pathogenic in ClinVar (CV ID 6035). The following publications have been ascertained in the context of this evaluation (PMID: 15146476, 11528398, 19596068, 16503651). ClinVar contains an entry for this variant (Variation ID: 286014). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Eurofins Ntd Llc (ga) RCV000494055 SCV000339267 uncertain significance not provided 2016-03-16 flagged submission clinical testing
Natera, Inc. RCV000675176 SCV001458431 likely pathogenic GNE myopathy 2020-09-16 no assertion criteria provided clinical testing

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