ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) (rs727503254)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000487427 SCV000564435 likely pathogenic Primary dilated cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy (PS4_Supporting; PMID:22464770; PMID:23054336; Partners LMM ClinVar SCV000204046). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:22464770; PMID:23054336; Partners LMM ClinVar SCV000204046). However, in another family, the variant did not segregate in two individuals with mild LV dysfunction (BS4; Partners LMM ClinVar SCV000204046). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. The benign evidence code BS4 was not considered to be in conflict with this conclusion given that the phenotype of the individuals without the variant did not match the expected presentation in variant carriers. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM1; PM2; PP1_Moderate; PS4_ Supporting; BS4
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000487427 SCV000204046 likely pathogenic Primary dilated cardiomyopathy 2017-12-08 criteria provided, single submitter clinical testing The p.Ala893Val variant in MYH7 has been detected in 4 individuals with DCM and segregated with disease in 5 affected family members (Lakdawala 2012, Miller 201 3, LMM data). It was absent from large population studies. This variant was clas sified as likely pathogenic on 12/15/2016 by the ClinGen-approved Inherited Card iomyopathy expert panel (ClinVar 177763). Computational prediction tools suggest that this variant may not impact protein function although this is not predicti ve enough to rule out pathogenicity. Of note, this variant lies in the head regi on of the protein. Missense variants in this region are significantly more likel y to cause disease (Walsh 2016). In summary, although additional studies are req uired to fully establish its clinical significance, the p.Ala893Val variant is l ikely pathogenic. ACMG/AMP Criteria applied: PM1;PM2;PP1_Moderate;PS4_ Supportin g;BS4
GeneDx RCV000154380 SCV000208493 uncertain significance not specified 2016-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The A893V variant has previously been reported in association with DCM (Lakdawala et al., 2012; Miller et al., 2013). Lakdawala et al. (2012) identified A893V in one individual with DCM, and subsequently found it segregated with disease in three other affected family members. In addition, this variant has also been observed in other unrelated individuals referred for DCM genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000204046.3; Landrum et al., 2016). The A893V 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A893V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position that is not conserved across species.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign
Invitae RCV000795089 SCV000934531 uncertain significance Hypertrophic cardiomyopathy 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 893 of the MYH7 protein (p.Ala893Val). 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 observed in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 29300372, 23054336) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). ClinVar contains an entry for this variant (Variation ID: 177763). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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