ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.773T>C (p.Leu258Ser) (rs876661377)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223695 SCV000565283 uncertain significance not specified 2017-05-23 criteria provided, single submitter clinical testing The L258S variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The L258S variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The L258S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (I263M, I263T, A259E, G256E, F252S, H251N) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223695 SCV000280378 uncertain significance not specified 2012-10-02 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Leu258Ser (L258S; c.773T>C) in the MYH7 gene We have seen this variant in a patient with RCM onset earleir than 3 years of age. This variant is completely novel, and has not been previously reported in patients with cardiomyopathy nor in general population controls. No segregation data is available. This is a non-conservative amino acid change, resulting in the replacement of a nonpolar Leucine with a polar Serine. The Leucine at this location is highely conserved across vertebrate species, although it is a Valine in some species of fish and a Glutamine in the scarlet macaw. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging” with a score of 0.935. Several nearby variants, within 10 amino acids to either side, have been reported in HGMD in association with hypertrophic cardiomyopathy, and in one case LVNC: Leu267Val, Tyr266Cys, Ile263Met, Ile263Thr, Ala259Glu, Gly256Glu, Phe252Cys, Phe252Leu, His251Asn, Arg249Gln. This supports the functional importance of this region of the protein. In total the variant has not been seen in ~60,000 individuals from publicly available population datasets. (Our patient has Mexican ancestry, so these are not all ethnicity-matched controls.) This variant is not present in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on 4300 Caucasian and 2200 African-American individuals (as of 1/26/2015). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. No variation at this codon is present in 1000 Genomes (http://browser.1000genomes.org) or dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as of 1/26/2015. Leu258Ser is also not present in ClinVar as of 6/11/2015. Our patient’s ancestry is Hispanic. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). It is absent from this database, which currently contains 5789 “Latino” individuals.

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