Submissions for variant NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)

dbSNP: rs121913632

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000678722	SCV000564428	pathogenic	Hypertrophic cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID: 8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). 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>C p.Gly741Arg - Variation ID 14098). 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; PP1_Moderate; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000678722	SCV000203910	likely pathogenic	Hypertrophic cardiomyopathy	2014-04-17	criteria provided, single submitter	clinical testing	The Gly741Trp variant in MYH7 has been reported in at least 3 individuals with H CM (Arai 1995, Perrot 2005, Pan 2012) and segregated with disease in 4 affected relatives from 2 families. This variant has also been previously identified by o ur laboratory in 5 individuals with HCM. It was absent from large population stu dies. Glycine (Gly) at position 741 is conserved in mammals, though not across evolutionarily distant species (birds and fish). The change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated b y our laboratory. This tool's pathogenic prediction is estimated to be correct 9 4% of the time (Jordan 2011). In addition, another variant at this position (Gly 741Arg) is reported to be disease-causing. In summary, although additional studi es are required to fully establish its clinical significance, the Gly741Trp vari ant is likely pathogenic.
GeneDx	RCV000158523	SCV000208458	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Identified in a multiple patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 8533830, 15856146, 23074333, 23283745, 24510615, 27532257, 30025578); 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: 23074333, 27247418, 8533830, 25935763, 21310275, 28606303, 15856146, 23283745, 24510615, 27532257, 24810389, 30025578, 29300372, 28166811, 29369293, 31737537, 32344918, 29907873, 31006259, 32746448, 32894683, 36252119, 37652022, 36243179, 35653365, 35288587, 26914223)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000678722	SCV000212638	pathogenic	Hypertrophic cardiomyopathy	2018-11-02	criteria provided, single submitter	research	This MYH7 Gly741Trp variant has been reported in mutliple HCM cases (Arai S, et al., 1995; Perrot A, et al., 2005; Otsuka H, et al., 2012; Santos S, et al., 2012; Pan S, et al., 2012; Kapplinger JD, et al., 2014; Walsh R, et al., 2017), and the variant was shown to segregate with disease in affected family members (Arai S, et al., 1995; Perrot A, et al., 2005). Interestingly, a variant at the same position resulting in a different amino acid change, Gly741Arg, has extensively reported in HCM cases (Fananapazir L, et al., 1993; Richard P, et al., 2003; Van Driest SL, et al., 2004; Song L, et al., 2005; Kaski JP, et al., 2009; Marsiglia JD, et al., 2013; Kapplinger JD, et al., 2014; Walsh R, et al., 2017). The MYH7 Gly741Trp variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), and the 1000 genomes project (http://www.1000genomes.org/). We have identified this variant in 5 HCM Probands. All four probands have a family history of disease, but segregation was only possible in 3 of these families and we found this variant to segregate in total of 4 affected first degree family members. In silico tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. 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. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 15 unrelated probands (PS4), segregates with disease in multiple families (PP1_strong), is located in a mutational hotspot (PM1), is rare in the general population (PM2), affects the same amino acid as another disease-causing variant (PM5), and is predicted to be deleterious by multiple in silico tools (PP3), therefore we classify MYH7 Gly741Trp as 'Pathogenic'.
Eurofins Ntd Llc (ga)	RCV000158523	SCV000226869	pathogenic	not provided	2015-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619837	SCV000739985	pathogenic	Cardiovascular phenotype	2021-04-13	criteria provided, single submitter	clinical testing	The p.G741W pathogenic mutation (also known as c.2221G>T), located in coding exon 18 of the MYH7 gene, results from a G to T substitution at nucleotide position 2221. The glycine at codon 741 is replaced by tryptophan, an amino acid with highly 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 variant has been described in several hypertrophic cardiomyopathy (HCM) cohorts and has been observed to co-segregate with disease in families (Arai S et al. Am J Med Genet. 1995;58:267-76; Perrot A et al. J Mol Med. 2005;83:468-77; Bagnall RD et al. J Am Coll Cardiol, 2018 07;72:419-429; Walsh R et al. Genet Med, 2017 02;19:192-203). In addition, another substitution at the same codon, p.G741R (c.2221G>A and c.2221G>C), has been described in multiple individuals with HCM (Fananapazir L et al. Proc Natl Acad Sci U.S.A. 1993;90(9):3993-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000678722	SCV000813145	pathogenic	Hypertrophic cardiomyopathy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the MYH7 protein (p.Gly741Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 8533830, 15856146, 22112859, 22429680, 25935763, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177665). 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 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). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000158523	SCV001433190	pathogenic	not provided	2020-01-07	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466449	SCV002761790	pathogenic	Hypertrophic cardiomyopathy 1	2021-03-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002466449	SCV005398121	pathogenic	Hypertrophic cardiomyopathy 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the myosin motor domain (NCBI, PMID: 29300372). (SP) 0702 - Another missense variant comparable to the one identified in this case has strong previous evidence for pathogenicity. An alternative change to arginine at the same residue has previously been reported as pathogenic in more than ten individuals with HCM (ClinVar, PMID: 27532257). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in more than ten individuals with HCM (ClinVar, VCGS, PMID: 27532257). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158523	SCV000280319	likely pathogenic	not provided	2015-09-09	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. MYH7 p.Gly741Trp (c.2221G>T) The variant has been seen in at least 9 unrelated individuals with HCM with moderately segregation data in one family. Arai et al (1995) reported a Japanese family with four individuals who all had HCM and carried p.Gly741Trp. The authors of that paper refer to an additional Japanese case, reported in a book chapter by Kimura et al (1994). Perrot et al (2005) reported two siblings from a German family who both had HCM and this variant. Santos et al (2012) observed the variant in one of 80 Portuguese patients with HCM. Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). It is not currently listed in ClinVar (as of October 3rd 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and mutationtaster predicts it 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.Gly741Arg (Van Driest et al 2004, we consider this variant very likely disease causing), p.Gly741Ala (primary data unavailable). 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 another variant at this codon, 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 ~6896 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 ~6500 Caucasian and African American individuals (as of 1 Oct 2014). The variant is listed in dbSNP (rs121913632), however the only submissions are OMIM and LMM (as of 1 October 2014). The variant is not listed in the 1000 genomes dataset (as of 1 October 2014). The variant was not observed in the following published control samples: 96 (Perrot et al 2005), 100 (Santos et al 2012), 200 (Bos et al 2014).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678722	SCV000804893	likely pathogenic	Hypertrophic cardiomyopathy	2016-03-16	no assertion criteria provided	clinical testing