ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.596C>T (p.Ala199Val) (rs727504283)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000706637 SCV000203951 pathogenic Hypertrophic cardiomyopathy 2015-04-29 criteria provided, single submitter clinical testing The p.Ala199Val variant in MYH7 has been identified by our laboratory in 3 indiv iduals with HCM (2 Caucasian and 1 Asian) and segregated with disease in 7 affec ted relatives from 1 family (including 3 obligate carriers; Pan 2012, LMM unpubl ished data and personal communication). The variant was absent from large popula tion studies. Alanine (Ala) at position 199 is highly conserved in mammals and a cross evolutionarily distant species and the change to valine (Val) was predicte d to be pathogenic using a computational tool clinically validated by our labora tory. This tool's pathogenic prediction is estimated to be correct 94% of the ti me (Jordan 2011). In summary, this variant meets our criteria to be classified a s pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/pe rsonalizedmedicine/LMM) based upon segregation studies and absence from controls .
GeneDx RCV000158746 SCV000208681 likely pathogenic not provided 2018-02-16 criteria provided, single submitter clinical testing The A199V likely pathogenic variant in the MYH7 gene has previously been reported in association with HCM (Alfares et al., 2015; Adler et al., 2016; Walsh et al., 2017). In addition, Pan et al. (2012) identified A199V in one patient with cardiomyopathy and found that this variant segregated with disease in >5 affected individuals within a single kindred, although specific segregation information was not provided. This variant was also identified in two unrelated individuals with childhood onset HCM referred for genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). Although the A199V 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 a deleterious effect. In addition, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018).
Invitae RCV000706637 SCV000835700 pathogenic Hypertrophic cardiomyopathy 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 199 of the MYH7 protein (p.Ala199Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID:  27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177692). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158746 SCV000280372 likely pathogenic not provided 2012-01-16 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.Ala199Val (c.596C>T). Data on this variant is reviewed below. We feel there is sufficiently strong co-segregation within the patient's own family to consider it likely pathogenic. I could find no published reports of this variant. Nearby missense variants have been reported in association with disease, including p.Ala196Thr (Woo et al 2003) and p.Arg204His (Richard et al 2003). The alanine at position 199 is completely conserved across species. In silico analysis with PolyPhen 2 predicts the variant to be probably damaging, while mutation taster predicts it to be disease causing. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~10,000 alleles from Caucasian and African American individuals (as of December 1st, 2011). It is not listed in dbSNP or 1000 genomes (as of December 1st, 2011).

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