ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.1892C>T (p.Ala631Val) (rs62541771)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000254883 SCV000613535 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing
Counsyl RCV000006406 SCV000678018 pathogenic GNE myopathy 2017-03-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254883 SCV000331895 pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763617 SCV000894471 pathogenic GNE myopathy; Sialuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000254883 SCV000321742 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The A662V variant in the GNE gene has been reported previously in association with autosomal recessive GNE-related myopathy when present in the homozygous state or when in trans with another disease-causing variant (Tomimitsu et al., 2002; Chaouch et al., 2014). Functional studies have shown that the A662V variant reduces GNE enzyme activity (Noguchi et al., 2004; Penner et al., 2006). The A662V variant is observed in 22/126688 (0.02%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The A662V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, we interpret A662V as a pathogenic variant.
Invitae RCV000763617 SCV000638331 pathogenic GNE myopathy; Sialuria 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 662 of the GNE protein (p.Ala662Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is clearly defined as a GNE myopathy causative allele (PMID: 24796702). It is a common cause of GNE myopathy in individuals of British and Chinese ancestry (PMID: 24695763, 22196754). This variant is also known as p.Ala631Val in the literature. ClinVar contains an entry for this variant (Variation ID: 6035). Experimental studies have shown that this missense change reduces the activity of the GNE-encoded protein, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (PMID: 14707127, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic.
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.
OMIM RCV000006406 SCV000026589 pathogenic GNE myopathy 2002-12-10 no assertion criteria provided literature only

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