ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4145G>A (p.Arg1382Gln) (rs727504325)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000560763 SCV000204083 likely pathogenic Hypertrophic cardiomyopathy 2018-09-12 criteria provided, single submitter clinical testing The p.Arg1382Gln variant in MYH7 has been identified in at least 15 individuals with HCM (Nunez 2013, Zou 2013, Walsh 2017, Kassem 2017, Ambry pers. comm., Invi tae pers. comm., GeneDx pers. comm., LMM data). It has also been reported by oth er clinical laboratories in ClinVar (Variation ID 177788) and has been identifie d in 1/15304 of African chromosomes by the Genome Aggregation Database (gnomAD, Computational prediction tools and conservati on analysis do not provide strong support for or against an impact to the protei n. In summary, although additional studies are required to fully establish its c linical significance, the p.Arg1382Gln variant is likely pathogenic. ACMG/AMP Cr iteria applied: PS4, PM2.
GeneDx RCV000766456 SCV000616801 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R1382Q variant has previously beenreported in association with HCM (Nunez et al., 2013; Sabater-Molina et al., 2013; Zou et al., 2013). However, thisvariant was also identified one individual without cardiovascular disease in the observational Jackson Heart Study(Bick et al., 2012). Nevertheless, the R1382Q variant is not observed in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1382Q variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ insome properties. This substitution occurs at a position that is conserved across species, and in silico analysis predictsthis variant is probably damaging to the protein structure/function.
Invitae RCV000560763 SCV000623715 uncertain significance Hypertrophic cardiomyopathy 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1382 of the MYH7 protein (p.Arg1382Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. The frequency data for this variant (rs727504325) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 23782526, 25132132, 27532257, 23283745). ClinVar contains an entry for this variant (Variation ID: 181389). 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: "Not Available"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000620123 SCV000736234 uncertain significance Cardiovascular phenotype 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Center for Human Genetics,University of Leuven RCV000560763 SCV000886837 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000766456 SCV000927533 likely pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766456 SCV001149173 likely pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing

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