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

gnomAD frequency: 0.00002  dbSNP: rs727504238

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000226806	SCV000203856	likely pathogenic	Hypertrophic cardiomyopathy	2019-10-15	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, Homburger 2016, LMM data). This variant has also been reported in ClinVar (Variation ID: 177625) and has been identified in 0.004% (1/24950) of African chromosomes and 0.003% (4/126704) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org;). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.His576Arg variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM1, PM2, PP3.
GeneDx	RCV000154204	SCV000208749	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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: 24111713, 27532257, 25611685, 15856146, 22958901, 20646679, 27247418, 28615295, 24835277, 23408646, 28606303, 28408708, 24033266, 27476098, 30645170, 30868567, 30847666, 31447099, 33065066, 32894683, 33673806, 29300372, 34542152, 34495297, 35653365, 36136372, 36264615, 36243179, 19666645)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000226806	SCV000223880	likely pathogenic	Hypertrophic cardiomyopathy	2019-01-16	criteria provided, single submitter	research	This MYH7 His576Arg variant has previously been observed in unrelated HCM cases (Perrot et al., 2005; Michels et al., 2009; van der Werf et al., 2010; Berge & Leren, 2014; Alfares et al., 2015). Segregation data is limited, however, Michels M, et al. (2009) identified this variant in one HCM index case as well as one family member that fulfilled diagnostic criteria for HCM. Van der Werf C, et al. (2010) identified MYH7 His576Arg in a 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 present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.000018. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2), has been reported in at least 6 HCM probands (PS4_Moderate) and multiple in silico tools predict this variant to have a deleterious affect (PP3), therefore we classify MYH7 His576Arg as "likely pathogenic".
Invitae	RCV000226806	SCV000284257	pathogenic	Hypertrophic cardiomyopathy	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 576 of the MYH7 protein (p.His576Arg). This variant is present in population databases (rs727504238, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15856146, 19666645, 20646679, 24111713, 27247418, 27532257, 28615295, 30847666, 30868567, 32894683, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 177625). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc.	RCV000172889	SCV000679781	likely pathogenic	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170510	SCV001333093	likely pathogenic	Cardiomyopathy	2018-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170510	SCV001343369	likely pathogenic	Cardiomyopathy	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 576 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 15856146, 19666645, 20646679, 24111713, 27247418, 27532257, 2840870, 286152958, 30847666, 33673806, 34542152; van der Werf 2010, dissertation, University of Virginia), and in an individual affected with an unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 5/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000172889	SCV001423553	likely pathogenic	Hypertrophic cardiomyopathy 1	2020-03-10	criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000154204	SCV002502781	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408684	SCV002716671	likely pathogenic	Cardiovascular phenotype	2022-10-07	criteria provided, single submitter	clinical testing	The p.H576R variant (also known as c.1727A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1727. The histidine at codon 576 is replaced by arginine, an amino acid with highly 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 has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8; van der Werf C et al. Heart Rhythm, 2010 Oct;7:1383-9; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505167	SCV002815835	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-05	criteria provided, single submitter	clinical testing