ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1727A>G (p.His576Arg) (rs727504238)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000226806 SCV000203856 likely pathogenic Hypertrophic cardiomyopathy 2016-10-20 criteria provided, single submitter clinical testing The p.His576Arg variant in MYH7 has been reported in at least 8 individuals and 1 family member with HCM (Perrot 2005, Michels 2009, Van der Werf 2010, Homburge r 2016, LMM data). This variant has also been reported by other clinical laborat ories in ClinVar (Variation ID: 177625) and has been identified in 1/24014 Afric an chromosomes and 4/126704 European chromosomes by the gnomAD Aggregation Conso rtium (gnomAD,; dbSNP rs727504238). Histidine ( His) at position 576 is highly conserved evolution and the change to arginine (A rg) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 94% of the time (Jordan 2011). In addition, this variant is located in the he ad domain of the MYH7 protein, which increases the likelihood that it is pathoge nic. In summary, although additional studies are required to fully establish its clinical significance, the p.His576Arg variant is likely pathogenic. ACMG/AMP C riteria applied (Richards 2015): PS4_Moderate, PM1, PP3, PM2.
GeneDx RCV000154204 SCV000208749 likely pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The H576R variant in the MYH7 gene has been reported in association with HCM in multiple publications (Perrot et al., 2005; Michels et al., 2009; van der Werf et al., 2010; Bick et al., 2012; Berge et al., 2014; Ingles et al., 2017; Ross et al., 2017; Walsh et al., 2017), though specific clinical details and segregation data are limited in many of these reports. This variant has also been identified in multiple individuals referred to GeneDx for HCM genetic testing. The H576R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). Nevertheless, the H576R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In summary, H576R in the MYH7 gene is interpreted as a likely pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000172889 SCV000223880 likely pathogenic Familial hypertrophic cardiomyopathy 1 2014-09-24 criteria provided, single submitter research This MYH7 His576Arg variant has previously been observed in unrelated HCM cases (Perrot A, et al., 2005; Michels M, et al., 2009; van der Werf C, et al., 2010). Segregation data is limited, however, Michels M, et al. (2009) identified this variant in one HCM index case and two asymptomatic family members. Clinical evaluation revealed one carrier to fulfil the diagnostic criteria for HCM (in the other carrier, only minor criteria were present). van der Werf C, et al. (2010) identified MYH7 His576Arg in an HCM family with a sudden unexplained death event (note: this family also carries a known pathogenic TNNT2 Arg102Trp variant). We have identified MYH7 His576Arg in one HCM proband with no family history of disease. Genetic analysis of parental samples reveal the presence of the variant in the mother, who is hypertensive and has mild concentric hypertrophy and does not meet the diagnostic criteria for HCM. This variant is absent in both the 1000 genomes project (, and occurs as a singleton event in the Exome Aggregation Consortium dataset ( Histamine (His) is highly conserved at position 576 across distantly related species. Although the amino acid substitution from His to Arg is considered to be conservative, multiple in silico tools are in agreement of a damaging effect: SIFT "deleterious"; PolyPhen2 "probably-damaging"; MutationTaster "disease-causing". Furthermore, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts MYH7 His576Arg to be pathogenic. Based on its rarity in the general population, and observation in multiple unrelated cases with the same disease, we classify this variant to be "likely pathogenic".
Invitae RCV000226806 SCV000284257 likely pathogenic Hypertrophic cardiomyopathy 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 576 of the MYH7 protein (p.His576Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs727504238, ExAC 0.01%). This variant has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15856146, 19666645, 24111713, 20646679, 27247418, 27532257), and in one HCM relative with myocardium deficiency (PMID: 24835277). Currently, there is not enough evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 177625). 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. 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 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.
Phosphorus, Inc. RCV000172889 SCV000679781 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000154204 SCV000927526 likely pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing

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