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

dbSNP: rs727503254

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000487427	SCV000564435	uncertain significance	Primary dilated cardiomyopathy	2021-09-22	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with DCM (PS4_Supporting; Lakdawala 2012 PMID:22464770; Miller 2013 PMID:23054336; LMM pers. comm.). This variant segregated with disease in 5 affected individuals with DCM in 2 families (PP1_Moderate; Lakdawala 2012 PMID:22464770; LMM pers. comm.); however, in one of these families the variant was absent from a set of identical twins with mild LV dysfunction prior to testing at 4 months of age and additional clinical data was not available. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient and conflicting evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM5_Moderate, PM2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000487427	SCV000204046	likely pathogenic	Primary dilated cardiomyopathy	2019-10-14	criteria provided, single submitter	clinical testing	The p.Ala893Val variant in MYH7 has been reported in 4 individuals with DCM and segregated with disease in 5 affected relatives from 3 families (Lakdawala 2012, Miller 2013, LMM data). It was absent from large population studies. Computational prediction tools suggest that this variant may not impact protein function although this is not predictive enough to rule out pathogenicity. Of note, this variant lies in the head region of the protein. Missense variants in this region are significantly more likely to cause disease (Walsh 2016). This variant has been classified as likely pathogenic on December 15, 2016 by the ClinGen-approved Inherited Cardiomyopathy expert panel (ClinVar variation ID: 177763). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala893Val variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PP1_Moderate, PS4_ Supporting.
GeneDx	RCV001699209	SCV000208493	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Reported in association with dilated cardiomyopathy (DCM) in the published literature (Lakdawala et al., 2012; Miller et al., 2013; Pugh et al., 2014; Kelly et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23074334, 29447731, 34935411, 27532257, 29300372, 22464770, 24503780, 23054336)
Invitae	RCV000795089	SCV000934531	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 893 of the MYH7 protein (p.Ala893Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with noncompaction cardiomyopathy and dilated cardiomyopathy (PMID: 22464770, 23054336, 27532257, 29300372, 29447731, 34935411; Invitae). ClinVar contains an entry for this variant (Variation ID: 177763). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002426736	SCV002744218	uncertain significance	Cardiovascular phenotype	2022-05-11	criteria provided, single submitter	clinical testing	The p.A893V variant (also known as c.2678C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2678. The alanine at codon 893 is replaced by valine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant was reported in a family with dilated cardiomyopathy (DCM), including three affected individuals and two young children who were asymptomatic at the time of evaluation (Lakdawala NK et al. J Card Fail, 2012 Apr;18:296-303; Lakdawala NK et al. Circ Cardiovasc Genet, 2012 Oct;5:503-10). This variant has also been reported in other DCM cohorts; however, clinical details were limited, and some individuals also had variants in other cardiac-related genes (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67;Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This variant was also reported in a non-compaction cardiomyopathy cohort (van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486688	SCV004239450	likely pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907459	SCV004724880	uncertain significance	MYH7-related condition	2023-12-14	criteria provided, single submitter	clinical testing	The MYH7 c.2678C>T variant is predicted to result in the amino acid substitution p.Ala893Val. This variant was reported in multiple individuals with dilated or noncompaction cardiomyopathy and was reported to segregate with disease in some families, although detailed information was not provided (Lakdawala et al. 2012. PubMed ID: 22464770; Table S1B, Walsh et al. 2016. PubMed ID: 27532257; Table S4, Kelly et al. 2018. PubMed ID: 29300372; Table 2a, van Waning et al. 2018. PubMed ID: 29447731; Table S2, Khan et al. 2021. PubMed ID: 34935411). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as uncertain by the ClinGen Cardiomyopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Clinical Genetics, Academic Medical Center	RCV001699209	SCV001925264	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699209	SCV001976344	likely pathogenic	not provided		no assertion criteria provided	clinical testing