ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2359C>T (p.Arg787Cys) (rs145677314)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000231165 SCV000050851 uncertain significance Hypertrophic cardiomyopathy 2017-01-04 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154774 SCV000204454 uncertain significance not specified 2017-09-08 criteria provided, single submitter clinical testing The p.Arg787Cys variant in MYH7 has been identified in 5 individuals with HCM (G arcia-Castro 2009, Coto 2012, Walsh 2017), 1 child with HCM, who also carried th e p.Arg97Cys variant in ACTC (Morita 2008), 1 adult with premature atrial contr actions (Ng 2013), and in 1 adult with ARVC, who carried another likely disease causing variant (LMM data). This variant has also been identified in 11/126688 E uropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs145677314). Arginine (Arg) at position 787 is not wel l conserved in mammals or evolutionarily distant species and the change to cyste ine (Cys) is present in 2 mammals (megabat and black flying fox). Additional com putational prediction tools do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the p.Arg787Cys vari ant is uncertain.
GeneDx RCV000766431 SCV000208465 uncertain significance not provided 2018-12-04 criteria provided, single submitter clinical testing The R787C variant of uncertain significance in the MYH7 gene has been reported previously in association with HCM (Morita et al., 2008; Garcia-Castro et al., 2009; Coto et al., 2012). This variant was initially identified in a child with early-onset hypertrophic cardiomyopathy (HCM) who also harbored a variant in the ACTC1 gene (Morita et al., 2008). Additionally, two adults with HCM were reported to harbor R787C, as well as an individual with premature atrial contractions and a family history of congenital aortic stenosis (Garcia-Castro et al., 2009; Coto et al., 2012; Ng et al., 2013). The R787C variant is observed in 3/34418 (0.009%) alleles from individuals of Latino background, and 14/277202 (0.005%) global alleles in large population cohorts (Lek et al., 2016). The R787C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Although another missense variant at this residue (R787H) has been reported in the Human Gene Mutation Database in association with HCM, the pathogenicity of that variant has not been definitively determined (Stenson et al., 2014). Nevertheless, the R787C variant lacks segregation data and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000231165 SCV000284261 uncertain significance Hypertrophic cardiomyopathy 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 787 of the MYH7 protein (p.Arg787Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs145677314, ExAC 0.009%). This variant has been reported in several individuals with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257). ClinVar contains an entry for this variant (Variation ID: 161327). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001114456 SCV001272340 likely benign Myopathy, distal, 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001114457 SCV001272341 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001114458 SCV001272342 likely benign Dilated cardiomyopathy 1S 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170276 SCV001332839 uncertain significance Cardiomyopathy 2018-05-15 criteria provided, single submitter clinical testing
Color RCV001170276 SCV001339613 uncertain significance Cardiomyopathy 2020-01-06 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148709 SCV000190439 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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