ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2858A>T (p.Asp953Val) (rs730880901)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158855 SCV000208790 pathogenic not provided 2012-02-10 criteria provided, single submitter clinical testing This mutation is denoted Asp953Val (aka D953V) at the protein level and c.2858 A>T at the cDNA level. The Asp953Val mutation in the MYH7 gene has not been previously reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. However a mutation in the same codon, (Asp953His) (Van Driest SL et al. 2004) and mutations in nearby codons (Glu949Lys, Leu961Arg) have been reported in association with HCM, supporting the functional importance of this residue and this region of the protein. Asp953Val results in a non-conservative amino acid substitution of a negatively charged Aspartic acid residue with a non-polar Valine residue. Furthermore, the NHLBI ESP Exome Variant Server reports Asp953Val was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Invitae RCV000226190 SCV000284271 uncertain significance Hypertrophic cardiomyopathy 2019-10-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 953 of the MYH7 protein (p.Asp953Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181380). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223789 SCV000280336 uncertain significance not specified 2012-06-04 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.Asp953Val (c.2858 A>T, D953V). The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The aspartate at codon 953 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Asp953His) and nearby codons (p.Glu949Lys, p.Leu961Arg). In total the variant has not been seen in ~6700 published controls and publicly available population datasets. There is no variation at codon 953 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 6/11/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 6/11/13).

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