ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.2086G>T (p.Val696Leu) (rs121908627)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000430334 SCV000225561 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000430334 SCV000321743 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing The V727L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V727L variant is observed in 90/66,620 (0.14%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and a different missense variant at the same position (V727M) has been reported in association with GNE myopathy (Eisenberg et al., 2001; Voermans et al., 2010). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Illumina Clinical Services Laboratory,Illumina RCV000277092 SCV000480086 likely benign GNE myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000315879 SCV000480087 likely benign Sialuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000372863 SCV000480088 likely benign Inclusion Body Myopathy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000430334 SCV000511635 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Invitae RCV000545813 SCV000632650 uncertain significance GNE myopathy; Sialuria 2019-11-24 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 727 of the GNE protein (p.Val727Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs121908627, ExAC 0.1%). This variant has not been reported in the literature in individuals with GNE-related disease. ClinVar contains an entry for this variant (Variation ID: 194025). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Val727Met) has been determined to be likely pathogenic (PMID: 25182749, 20175955, 24005727, 21708040, 11528398, 12497639). This suggests that the valine residue is critical for GNE protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000430334 SCV000693291 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing

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