Submissions for variant NM_000257.4(MYH7):c.2221G>A (p.Gly741Arg)

gnomAD frequency: 0.00003  dbSNP: rs121913632

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461730	SCV000059429	likely pathogenic	Hypertrophic cardiomyopathy	2014-04-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158521	SCV000208456	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	Reported in several other individuals with HCM; however, the nucleotide change was not specified (Malinchik et al., 1997; Van Driest et al., 2004; Kaski et al., 2009; Theis et al., 2009; Kindel et al., 2012; Marsiglia et al., 2013; Miller et al., 2013; Berge et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#42890; ClinVar); This variant is associated with the following publications: (PMID: 15358028, 7731997, 22555271, 21216834, 9742053, 20031618, 19808356, 12707239, 25935763, 24093860, 9140824, 8483915, 15563892, 26743238, 28246639, 27247418, 27532257, 29101517, 24111713, 29343710, 23054336, 24704860)
Ambry Genetics	RCV000243586	SCV000320678	pathogenic	Cardiovascular phenotype	2022-02-18	criteria provided, single submitter	clinical testing	The p.G741R pathogenic mutation (also known as c.2221G>A), located in coding exon 18 of the MYH7 gene, results from a G to A substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with dissimilar 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 alteration, and a different nucleotide substitution resulting in the same amino acid change (c.2221G>C), were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) (Fananapazir L, Proc. Natl. Acad. Sci. U.S.A. 1993 May; 90(9):3993-7; Montag J et al. J. Muscle Res. Cell. Motil. 2017 Aug;38(3-4):291-302). The p.G741R alteration has been reported in multiple additional HCM cohorts (Richard P, Circulation 2003 May; 107(17):2227-32; Van Driest SL, J. Am. Coll. Cardiol. 2004 Aug; 44(3):602-10.; Song L, Clin. Chim. Acta 2005 Jan; 351(1-2):209-16; Kindel SJ, J. Card. Fail. 2012 May; 18(5):396-403; Marsiglia JD, Am. Heart J. 2013 Oct; 166(4):775-82; Berge KE, Clin. Genet. 2014 Oct; 86(4):355-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, another alteration involving the same amino acid (p.G741W, c.2221G>T) has also been reported in association with HCM (Arai S et al. Am J Med Genet. 1995;58:267-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461730	SCV000546276	pathogenic	Hypertrophic cardiomyopathy	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). This variant is present in population databases (rs121913632, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 20800588, 24111713, 25935763). ClinVar contains an entry for this variant (Variation ID: 42890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly741 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8533830, 15856146, 22112859, 26914223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170500	SCV001333083	pathogenic	Cardiomyopathy	2022-04-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534738	SCV004119604	pathogenic	MYH7-related disorder	2022-11-22	criteria provided, single submitter	clinical testing	The MYH7 c.2221G>A variant is predicted to result in the amino acid substitution p.Gly741Arg. This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Fananapazir et al. 1993. PubMed ID: 8483915; Table S1, Captur et al. 2014. PubMed ID: 24704860; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Filatova et al. 2021. PubMed ID: 34598319). Functional studies in patient-derived muscle fibers showed that the p.Gly741Arg substitution could alter the contractile properties of the mutant protein (Lankford and Fananapazir. 1995. PubMed ID: 7883988). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23894969-C-T). Other different nucleotide substitutions affecting the same amino acid (p.Gly741Trp and p.Gly741Ala) have been reported in individuals with hypertrophic cardiomyopathy (Arai et al. 1995. PubMed ID: 8533830; Van Driest et al. 2004. PubMed ID: 15358028). The c.2221G>A (p.Gly741Arg) variant is interpreted as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158521	SCV000280318	pathogenic	not provided	2014-07-15	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly741Arg in the MYH7 gene. This variant has been seen in at least 9 cases of HCM. Fananapazir (1993) reported the variant in two unrelated families with HCM; the variant co-segregated with HCM in three affected members of one family and two affected members of the other family. Song et al (2005) observed the variant arising de novo in an individual with HCM. Richard et al (2003) reported the variant in one individual with HCM. Millat et al (2010) reported the identification of this variant in a cohort of individuals studied using high resolution melting to identify variants (this case may be redundant with the Richards et al case as both came from French cohorts). Keller et al (2005) reported the variant in a woman with HCM in their Swiss cohort. Kaski et al (2009) observed the variant in two unrelated children with HCM in a British cohort. We have also observed this variant in another patient with HCM in our clinic. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Ala (primary data unavailable), p.Gly741Trp (we consider this variant likely disease causing). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that p.Gly741Arg confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6,720 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). There is also no variation at codon 741 listed in dbSNP or 1000 genomes (as of 9/20/13). The variant was not observed in the following published control samples: 120 general population individuals studied by Song et al (2005) (likely Chinese ancestry), 100 healthy adults reported by Richard et al (2003). No further control data was provided by GeneDx or the other authors cited above.