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

dbSNP: rs121913632

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000472342	SCV000564427	pathogenic	Hypertrophic cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>T p.Gly741Trp - Variation ID 177665). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PM6; PP1; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000472342	SCV000059430	likely pathogenic	Hypertrophic cardiomyopathy	2015-10-16	criteria provided, single submitter	clinical testing	The p.Gly741Arg variant has been reported in >10 individuals with HCM, occurred de novo in one of them, and segregated with disease in 3 affected relatives from 2 families (Fananapazir 1993, Malinchik 1997, Richard 2003, Van Driest 2004, So ng 2005, Kaski 2009, LMM unpublished data). It has not been identified in large population studies. This variant was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , this variant is likely pathogenic.
GeneDx	RCV000158522	SCV000208457	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Published functional studies evaluating the contractile properties of single slow-twitch muscle fibers from patients with this variant demonstrate that G741R results in decreased maximum velocity of fiber shortening and decreased isometric force generation, suggesting this variant has a damaging effect on the protein (Lankford et al., 1995); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7731997, 24093860, 27532257, 27476098, 31006259, 33642254, 15563892, 20031618, 8483915, 15358028, 12707239, 28246639, 27247418, 24111713, 29300372, 24704860, 32710294, 25935763, 32894683, 7883988)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000015154	SCV000256140	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Invitae	RCV000472342	SCV000546223	pathogenic	Hypertrophic cardiomyopathy	2023-11-09	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 not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 15358028, 15563892, 20031618, 24093860, 24111713, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14098). 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%. 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). 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.
Ambry Genetics	RCV000621362	SCV000740146	pathogenic	Cardiovascular phenotype	2018-11-28	criteria provided, single submitter	clinical testing	The p.G741R pathogenic mutation (also known as c.2221G>C), located in coding exon 18 of the MYH7 gene, results from a G to C substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and a different nucleotide substitution (c.2221G>A) resulting in the same amino acid change were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) including a reported de novo occurrence (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 et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Song L et al. Clin Chim Acta. 2005;351(1-2):209-16; Kindel SJ et al. J Card Fail. 2012;18(5):396-403; Marsiglia JD et al. Am Heart J. 2013;166(4):775-82; Berge KE et al. Clin Genet 2014;86(4):355-60). 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000472342	SCV000996368	pathogenic	Hypertrophic cardiomyopathy	2017-06-14	criteria provided, single submitter	research	The MYH7 Gly741Arg (c.2221G>C) has been reported in more than 10 unrelated HCM probands and has been found to cosegregate in a few cases (see literature). Song L, et al., (2005), reported 1 HCM where the variant arose de novo. We identified this variant in 1 HCM proband of Middle Eastern descent, with a strong family history of disease in the family, however genetic testing was only possible for one affected sibling who was also found to harbour the variant. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools, SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Furthermore functional studies suggest that the variant results in decreased velocity of shortening and reduced isometric force generation (Lankford EB, et al., 1995). 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. Furthermore variant located in the converter region of MYH7 (amino acids 709-777) are predicted to result in worse outcomes (Garcia-Giustiniani D, et al., 2015). Interestingly, a different rare variant at this position (Gly741Trp) has also been classified as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. In summary based on this evidence we classify MYH7 Gly741Arg as 'Pathogenic'.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170499	SCV001333082	pathogenic	Cardiomyopathy	2019-02-12	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000472342	SCV001449021	pathogenic	Hypertrophic cardiomyopathy	2016-03-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490371	SCV002793972	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	2021-09-26	criteria provided, single submitter	clinical testing
OMIM	RCV000015154	SCV000035411	pathogenic	Hypertrophic cardiomyopathy 1	1993-05-01	no assertion criteria provided	literature only