ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 768 of the MYH7 protein (p.Gly768Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) (PMID: 12707239, 18076673, 20394946, 20800588, 22260945, 25935763; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164337). 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.

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.

The p.G768R pathogenic mutation (also known as c.2302G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2302. The glycine at codon 768 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 has been reported in multiple individuals, including a pair of monozygotic twins, with hypertrophic cardiomyopathy (HCM), and once as a de novo occurrence in an individual with restrictive cardiomyopathy (RCM) (Ho CY et al. Circ Cardiovasc Imaging, 2013 May;6:415-22; García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53; Walsh R et al. Genet. Med., 2017 02;19:192-203; Wang J et al. Int Heart J, 2019 Mar;60:477-481; Franaszczyk M et al. J Clin Med, 2020 Jan;9). In addition, a different alteration located at the same position, resulting in the same protein change, c.2302G>C (p.G768R), has been reported in individuals with HCM and RCM (Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24; Ware SM et al. Clin. Genet., 2008 Feb;73:165-70; Hinton RB et al. J. Pediatr., 2010 Jul;157:164-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Found to segregate with HCM in two unrelated families referred for genetic testing at GeneDx and reported to segregate with an HCM or RCM phenotype with the age of onset ranging from infancy to adulthood in the published literature (Hinton et al., 2010); 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: 23054336, 25524337, 34057638, 33429969, 31324451, 31737537, 25935763, 17125710, 20738943, 22260945, 23690394, 23549607, 18076673, 22555271, 20031602, 27247418, 20624503, 27600940, 28606303, 27532257, 28831623, 30165862, 30745532, 32013205, 20394946, 27535533, 12707239, 33906374, 33658374, 29300372)

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).