ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3676C>G (p.Leu1226Val) (rs876661211)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217474 SCV000279799 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing The L1226V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where only amino acids with similar properties to Leucine are tolerated across species. However, the L1226V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000806088 SCV000946069 uncertain significance Hypertrophic cardiomyopathy 2019-05-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1226 of the MYH7 protein (p.Leu1226Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 234775). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256684 SCV001433078 uncertain significance Dilated cardiomyopathy 1A 2019-09-19 criteria provided, single submitter clinical testing

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