ClinVar Genomic variation as it relates to human health

The c.2156G>A (p.Arg719Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:7848441; PMID:16199542; PMID:15358028; PMID:18411228; Partners LMM ClinVar SCV000059421.5; AGCMC Sydney ClinVar SCV000212634.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:7848441; Partners LMM ClinVar SCV000059421.5). 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.2155C>T p.Arg719Trp ClinVar Variation ID 14104). 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; PP1_ Strong; PM1; PM2; PM5; PP3

This MYH7 Arg719Gln mutation has previously been described in multiple HCM cohorts (see references). It was first reported in a Hispanic family with HCM (Consevage MW, et al., 1994) and has been detected in individuals of other ethnic backgrounds (Moolman-Smook JC, et al., 1999; Huang X, et al., 2001; Marsiglia JD, et al., 2013). This mutation has been shown to cosegregate with disease, however, disease espressivity is variable. Many reports have described the clinical characteristics of this MYH7 Arg719Gln mutation with early-onset disease (Consevage MW, et al., 1994) and/or a positive family history of sudden cardiac death events (Huang X, et al., 2001; Van Driest SL, et al., 2004; Fokstuen S, et al., 2008; Morita H, et al., 2008). This mutation occurs at a known hotspot region of the MYH7 gene and a different HCM causing mutation at this position (Arg719Trp) has been documented (Tesson F, et al., 1998; Marsiglia JD, et al., 2013). In our cohort, we have identified two HCM index cases with this Arg719Gln mutation, of which one case was identified to be a double heterozygote with another mutation in the MYBPC3 gene (Ingles J, et al., 2005). Based on literature evidence, familial segregation analysis, and absence in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), we classify this variant as "pathogenic".

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.93). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15358028 , 16199542 , 18411228 , 30297972 , 7848441). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 7848441). Different missense changes at the same codon (p.Arg719Pro, p.Arg719Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014104 , VCV000217460). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The MYH7 c.2156G>A; p.Arg719Gln variant (rs121913641) is reported in the literature in multiple individuals and families with hypertrophic cardiomyopathy, and shown to co-segregate with disease (Burns 2017, Consevage 1994, Gonzalez-Quereda 2020, Robyns 2020, Walsh 2017). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 14107). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 719 is highly conserved, and computational analyses are uncertain whether this variant is benign or deleterious (REVEL: 0.694). Based on available information, this variant is considered to be pathogenic. References: Burns C et al. Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. Circ Cardiovasc Genet. 2017 Aug;10(4):e001666. PMID: 28790153. Consevage MW et al. A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. Hum Mol Genet. 1994 Jun;3(6):1025-6. PMID: 7848441. Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. Robyns T et al. Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. Eur J Med Genet. 2020 Mar;63(3):103754. PMID: 31513939. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.

Identified in multiple unrelated individuals diagnosed with HCM from various ethnic backgrounds (Consevage et al., 1994; Moolman-Smook et al., 1999; Van Driest et al., 2002; Richard et al., 2003; Van Driest et al., 2004; Ingles et al., 2005; Fokstuen et al., 2011; Kassem et al., 2013; Liu et al., 2013; Marsiglia et al., 2013; Nunez et al., 2013; Kapplinger et al., 2014; Rubattu et al., 2016; Burns et al., 2017); Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564422.4; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate reduced actin filament velocity and mouse models show pathologic remodeling in cardiac tissue (Yamashita et al., 2000; Teekakirikul et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15858117, 27483260, 27532257, 27247418, 31006259, 18411228, 12473556, 12707239, 11968089, 15358028, 16199542, 18403758, 19645038, 20811150, 20309391, 20800588, 23233322, 24510615, 23782526, 24093860, 11498078, 10521296, 23711808, 21239446, 27590665, 21310275, 28323875, 28790153, 29300372, 31513939, 32403337, 30847666, 32894683, 33673806, 7848441, 10882745)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 719 of the MYH7 protein (p.Arg719Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 7848441, 15358028, 15519027, 15858117, 16199542, 18409188, 21896538, 23140321, 23711808). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14107). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 10882745). This variant disrupts the p.Arg719 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8282798, 20811150, 21310275). 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.

The p.R719Q pathogenic mutation (also known as c.2156G>A), located in coding exon 17 of the MYH7 gene, results from a G to A substitution at nucleotide position 2156. The arginine at codon 719 is replaced by glutamine, an amino acid with highly similar properties, and is located in the head domain. This alteration was reported to co-segregate with hypertrophic cardiomyopathy (HCM) in one family, and was reported as an apparent de novo occurrence in a proband with HCM (Consevage MW et al. Hum Mol Genet. 1994;3(6):1025-6; Garcia-Pavia P et al. Eur J Heart Fail. 2011;13(11):1193-201). This mutation has been reported in multiple HCM cohorts in unrelated individuals with HCM, some with early-onset disease or a family history of HCM and sudden death (Moolman-Smook JC et al. Am. J. Hum. Genet., 1999 Nov;65:1308-20; Huang X et al. Clin Chim Acta. 2001;310(2):131-9; Kapplinger JD et al. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Rubattu S et al. Int J Mol Sci, 2016 Jul;17; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

proposed classification - variant undergoing re-assessment, contact laboratory

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.Arg719Gln (R719Q; c.2156G>A) in the MYH7 gene As of our first review in 2012, this variant had been reported in at least 11 unrelated cases of HCM with moderate segregation data in 1 family (4 individuals) and no functional studies. (Our literature search has not been updated since 2012.) Consevage et al. (1994) first reported this variant in a Hispanic family. It segregated with disease in all 4 affected family members (a child, parent, grandparent, and uncle), with the greatest separation being 2nd degree relatives. Moolman-Smook (1999) identified it in a South African patient of northern-European descent. Huang et al. (2001) identified it in a Chinese family. Van Driest et al. (2002) identified it in 2 unrelated HCM patients at the Mayo Clinic. Waldmuller et al. (2002) used this variant in developing a microarray screen for recurring HCM variants. Richard et al. (2003) identified Arg719Gln in one HCM patient recruited in France. Van Driest et al. (2004) reported a case of a patient with a double variant: Arg719Gln and Thr1513Ser (phase unknown); they also reported 2 additional, unrelated patients…but it’s unclear if these are the 2 from 2002. Ingles et al. (2005) found the variant in an Australian double heterozygote who also carried an Arg273His variant in MYBPC3. Her son inherited both variants along with the disease. Yu et al. (2005) found Arg719Gln in two unrelated Australian families. Morita et al. (2008) found it in one HCM case. Wang et al. (2008) found it in at least one Chinese HCM case. Harris et al. (2010) found it in cis with a T1513S MYH7 variant in an HCM patient and her affected mother. Garcia-Pavia et al. (2011) found it in one HCM proband in Spain. This variant is listed in ClinVar, and it is classified as pathogenic by Harvard’s Laboratory for Molecular Medicine which reports seeing it in 12 families. LMM also reports that it did segregate with disease in their internal data. Other changes at this same codon, Arg719Trp and Arg719Pro, have been associated with HCM (Harvard Sarcomere Protein Gene Mutation Database). Variation at nearby loci of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Pro710Arg, Pro710His, Arg712Leu, Gly716Ala, Gly716Arg, Arg721Lys, Arg723Cys, Arg723Gly, Arg723His, and Ala728Val (GeneDx report). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Glutamine. The Arginine at codon 719 is highly conserved across 41 vertebrate species examined (it is a Lysine in 7 species: Chicken, Tetraodon, Fugu, Stickleback, Medaka, Zebrafish, and Lamprey). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging”. The residue is in a domain that has been proposed to interact with the myosin light chains, a domain adjacent to the invariant SH1/SH2 domain (Rayment et al. 1995). In total the variant has not been seen in >60,000 published controls and publicly available population datasets. There is no variation at codon 719 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 6/16/2015). There is also no variation at this codon listed in 1000 genomes (as of 6/16/2015). The variant was not observed in published controls: Consevage et al. (1994) did not observe it in 42 controls. Moolman-Smook (1999) did not observe it in 100 controls. Huang et al. (2001) did not find it in 60 Chinese controls. Van Driest et al. (2002) did not report controls. Richard et al. (2003) did not find the variant in 100 (European?) controls. Van Driest et al. (2004) did not observe the variant in 100 Caucasian and 100 African American controls. Ingles et al. (2005) did not find it in 150 (Australian?) controls. Yu et al. (2005) did not find it in 100 Australian controls matched for ethnicity. Morita et al. (2008) did not find it in 180 ethnicity-matched controls. Garcia-Pavia et al. (2011) did not find it in 200 Spanish controls. Our patient’s ancestry is from Mexico. Ancestry-matched individuals can be found in greater numbers in the ExAC database of ~60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). This variant is not present in ExAC, which currently contains calls on 5786 “Latino” individuals.