ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.728G>A (p.Arg243His) (rs267606910)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000514633 SCV000208691 likely pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the MYH7 gene. The R243H variant was initially reported in one individual with apical HCM and was absent from approximately 200 control alleles (Arad et al., 2005). Subsequently, R243H was shown to segregate with LVNC in four related individuals (Klaassen et al., 2008). The R243H variant has also been identified independently in several unrelated individuals affected with LVNC and referred for cardiomyopathy testing at GeneDx. R243H is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Moreover, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Walsh et al., 2017; Kelly et al., 2018). Specifically, a missense variant in the same residue (R243C), and multiple missense variants in nearby residues (D239N, F244L, F244C, K246Q, K246I, F247L, I248T), have been reported in the Human Gene Mutation Database (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. However, the R243H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. And to our knowledge, no studies have been performed to determine the functional effect of the R243H variant.
Invitae RCV000472129 SCV000546234 pathogenic Hypertrophic cardiomyopathy 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 243 of the MYH7 protein (p.Arg243His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs267606910, ExAC 0.001%). This variant has been reported in several individuals with left ventricular non-compaction cardiomyopathy (LVNC) and to segregate with the disease (PMID: 18506004, 20965760, 21551322). ClinVar contains an entry for this variant (Variation ID: 14126). 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, this is a rare missense variant which has been reported in affected individuals and is predicted to cause a deleterious effect on MYH7 protein function. For these reasons it has been classified as Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514633 SCV000611019 uncertain significance not provided 2017-04-19 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000015186 SCV000679796 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000472129 SCV000967720 likely pathogenic Hypertrophic cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing The p.Arg243His variant in MYH7 has been reported in 1 individual with hypertrop hic cardiomyopathy (Arad 2005), 1 with Ebstein anomaly (Sicko 2016), and 1 with left ventricular non-compaction, where it segregated in two affected relatives ( Klaassen 2008). It has been identified in 1/111714 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs2 67606910) and has been reported in ClinVar (Variation ID: 14126). In addition, another amino acid substitution involving this codon, p.Arg243Cys, has also been identified in individuals with HCM (Kubo 2011, Homburger 2016, Viswanathan 2017 ). Computational prediction tools and conservation analysis suggest that the p.A rg243His variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. This variant lies in the head region of th e protein and missense variants in this region have been reported and statistica lly indicated to be more likely to cause disease (Walsh 2016). In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Arg243His variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3.
OMIM RCV000015186 SCV000035443 pathogenic Familial hypertrophic cardiomyopathy 1 2008-06-03 no assertion criteria provided literature only
OMIM RCV000015187 SCV000035444 pathogenic Left ventricular noncompaction 5 2008-06-03 no assertion criteria provided literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656213 SCV000678407 likely pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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