ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1012G>A (p.Val338Met) (rs727503271)

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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 RCV000792549 SCV000199244 likely pathogenic Hypertrophic cardiomyopathy 2014-11-20 criteria provided, single submitter clinical testing The p.Val338Met variant in MYH7 has been identified by our laboratory in 2 indiv iduals with HCM and segregated with disease in 5 affected relatives from 1 famil y. Of note, affected individuals are reported to have varying ages of onset (age 3 - 50's). This variant was also identified in 2 teenagers with early signs of left ventricular wall thickening and in 3 asymptomatic obligate carriers. This v ariant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong evidence for or against an impac t to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val338Met variant is likely pathogeni c.
GeneDx RCV000158778 SCV000208713 likely pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing The V338M likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Valente et al., 2013; Captur et al., 2014; Walsh et al., 2017). This variant has also been classified as a likely pathogenic variant and reported to segregate with disease in multiple members from one family by another clinical laboratory in ClinVar (SCV000199244.4; Landrum et al., 2016). The V338M variant is not observed in large population cohorts (Lek et al., 2016). A missense variant in the same residue (V338A) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Furthermore, the V338M variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). However, the V338M 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 that this variant does not alter protein structure/function. In summary, V338M in the MYH7 gene is interpreted as a likely pathogenic variant.
Invitae RCV000792549 SCV000931853 uncertain significance Hypertrophic cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 338 of the MYH7 protein (p.Val338Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257) and in an unaffected individual whose relative had hypertrophic cardiomyopathy (PMID: 23690394). ClinVar contains an entry for this variant (Variation ID: 164381). 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"). 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). 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 RCV000158778 SCV000280291 likely pathogenic not provided 2013-04-17 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.Val338Met (c.1012G>A) in MYH7. We have seen this variant in a family with HCM and it was present in multiple affected family members. The variant has been seen in a total of two unrelated HCM case (including the family in our center). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The valine at codon 338 is highly, though not completely, conserved across species; it is an isoleucine in platypus, chicken, and lizard. Neighboring amino acids are completely or highly conserved. We ere unable to find other variants reported in association with disease at this codon or nearby codons (+/- 5 positions). In total the variant has not been seen in ~6500 publicly available population datasets. There is no variation at codon 338 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 6th, 2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 6th, 2012). No published or laboratory control data is available.

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