ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg) (rs727503260)

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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 RCV000151276 SCV000199202 pathogenic Restrictive cardiomyopathy; Hypertrophic cardiomyopathy 2017-09-04 criteria provided, single submitter clinical testing The p.Gly768Arg variant in MYH7 has been reported in 13 individuals with HCM, HC M with RCM, HCM with LVNC, or RCM, and segregated with disease in 5 affected rel atives from 3 families (Richard 2003, Laredo 2006, Ware 2008, Hinton 2010, Ho 20 13, Walsh 2014, Coppini 2014, Garcia-Giustiniani 2015, LMM data). It has not bee n identified in large population studies. Glycine (Gly) at position 768 is highl y conserved in mammals and across evolutionarily distant species and the change to arginine (Arg) was predicted to be pathogenic using a computational tool clin ically validated by our laboratory. This tool's pathogenic prediction is estimat ed to be correct 94% of the time (Jordan 2011). In summary, this variant meets c riteria to be classified as pathogenic for cardiomyopathy in an autosomal domina nt manner based upon prevalence in affected probands, segregation with disease, predicted functional impact, and extremely low frequency in the general populati on.
GeneDx RCV000158526 SCV000208461 pathogenic not provided 2018-03-19 criteria provided, single submitter clinical testing The G768R pathogenic variant in the MYH7 gene (as a result of a G>C or G>A nucleotidesubstitution) has been reported previously in association with HCM (Richard et al., 2003; Laredo et al., 2006; Barriales-Villa et al., 2010; Hinton et al., 2010; Kindel et al., 2012; Coppini et al., 2014; Walsh et al., 2017). This variant has also been reported in association with restrictive cardiomyopathy (RCM) (Ware et al., 2008; Walsh et al.,2012). In one reported family, the G768R variant segregated with an HCM or RCM phenotype and the age of onset ranged from infancy to adulthood (Hinton et al., 2010). This variant has been shown to segregate with disease in several unrelated families referred for genetic testing at GeneDx and at another clinical laboratory in ClinVar(SCV000199202.3; Landrum et al., 2016). The G768R variant is not observed in large population cohorts (Lek et al., 2016). The G768R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, G768R in the MYH7 gene is interpreted as a pathogenic variant.
Invitae RCV000462424 SCV000546207 pathogenic Hypertrophic cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 768 of the MYH7 protein (p.Gly768Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) and to segregate with the disease in two families (PMID: 12707239, 18076673, 20394946, 22260945, 25935763). ClinVar contains an entry for this variant (Variation ID: 164337). A different variant (c.2302G>C) giving rise to the same protein effect observed here (p.Gly768Arg) has also been reported in an individual affected with HCM (PMID: 20800588). 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, this variant is absent from population databases, is predicted to be deleterious, and has been shown to segregate with cardiomyopathy. For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc. RCV000578019 SCV000679784 pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621337 SCV000740266 likely pathogenic Cardiovascular phenotype 2017-12-08 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158526 SCV000280320 pathogenic not provided 2012-01-18 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.Gly768Arg (c.2302 G>A) in the MYH7 gene (NM_000257.2). The variant has been seen in at least 7 unrelated cases of familial cardiomyopathy (not including this patient's family). There is strong segregation data in one family. The Seidmans' online database notes that in 2001 they observed the variant in two affected members of a family with HCM (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_Gly768Arg.html). They also note a "direct submission" to them by Gruver et al 2001, with no details on phenotype, ancestry, or segregation. The Seidmans' family is presumably the same family they include in later publications (Ho et al 2002, Valente et al 2013). Richard et al (2003) observed the variant in one of 197 unrelated HCM patients from their French cohort who had sequencing of 9 sarcomere genes. They note most patients were of European origin. Segregation data was not provided. Millat et al (2010) observed the variant in one of 192 unrelated French HCM patients. This appears to be a distinct cohort from that studied by Richard et al (the authors do not overlap and Millat et al reference Richard et al as if it was an independent study). No ancestry or segregation data were provided. Stephanie Ware's group reported a family with both HCM and restrictive cardiomyopathy with this variant (Ware et al 2008 and Hinton et al 2010). Affected first cousins both carried the variant. The male proband had infantile onset restrictive cardiomyopathy and was transplanted soon after diagnosis. The proband's aunt had HCM and had a baby with in utero onset of HCM who died on the first day of life and had sequencing of 8 sarcomere genes, which revealed on p.Gly768Arg. This appears to be the same case later reported by this group in a study on restrictive cardiomyopathy and conduction system disease (Walsh et al 2012). Interestingly, the same group also reported what appear to be two additional unrelated cases of HCM with this variant in a series of patients with pediatric cardiomyopathy who underwent genetic evaluation (Kindel et al 2012). One patient had HCM, presented at 10yo and had genetic testing at 14yo and had a family hsitory of cardiomyopathy and sudden death. The other presented at 2yo and had genetic tesitng at 3yo. Laredo et al (2006) observed the variant in one of 128 HCM patients in their Spanish cohort. I found a poster online from the same group that presumably describes the same case(Garcia-Giustiniani et al 2014, European Society of Cardiology http://spo.escardio.org/eslides/view.aspx?eevtid=54&fp=P4868). In the 2006 paper they report on a single affected family member with the variant, however in the 2014 poster they note there were six family members who have HCM and carry the variant. It is not currently in ClinVar (July 9th, 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.992). This is a non-conservative amino acid change with a Grantham score of 125. The glycine at codon 768 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Val763Gly, Phe764Leu, Phe764Tyr, Lys766Asn, Glu774Val, Asp778Gly, Asp778Val, Asp778Glu (in HGMD, per GeneDx report; Seidmans' database http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_mutations_TOC.html)). In total the variant has not been seen in ~6600 published controls and individuals from publicly available population datasets. There is no variation at codon 768 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 9th, 2014). Note that this dataset does not match the patient's ancestry (Hawaiin). There is also no variation at this codon listed in dbSNP (as of July 9th, 2014). The variant was not observed in the following published control samples: 100 healthy adults (Richard et al 2003).

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