ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln) (rs121913641)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000468000 SCV000564422 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation 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; 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
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000468000 SCV000059421 pathogenic Hypertrophic cardiomyopathy 2018-02-20 criteria provided, single submitter clinical testing The p.Arg719Gln variant has been identified in >20 individuals with HCM (Conseva ge 1994, Moolman-Smook 1999, Huang 2001, Van Driest 2002, Richard 2003, Van Drie st 2004, Ingles 2005, Fokstuen 2008, LMM data), has segregated with disease in 6 affected family members (Consevage 1994, LMM data), and was absent from large p opulation studies. Consistent with this evidence, the p.Arg719Gln variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Finally, a different change at this position (p.Arg719Tr p) is also known to be pathogenic. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon its presence in multiple affected individuals, segregation studies, absence from co ntrols, and computational predictions. ACMG/AMP Criteria applied: PS4; PP1_Moder ate; PM5; PP3_Moderate.
GeneDx RCV000158513 SCV000208448 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing The R719Q pathogenic variant in the MYH7 gene has been reported 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). This variant has been reported to segregate with early-onset HCM in three relatives from one Hispanic family (Consevage et al., 1994). Additionally, it segregated with HCM in affected individuals from unrelated families referred for genetic testing at GeneDx. R719Q has been reported as an apparently de novo variant in a patient with HCM previously tested at GeneDx. The R719Q variant is not observed in large population cohorts (Lek et al., 2016).The R719Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies show that R719Q results in reduced actin filament velocity and mouse models of R719Q show pathologic remodeling in cardiac tissue (Yamashita et al., 2000; Teekakirikul et al., 2010). Finally, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018).In summary, R719Q in the MYH7 gene is interpreted as a pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015163 SCV000212634 pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter research 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 (, we classify this variant as "pathogenic".
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000015163 SCV000256125 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250394 SCV000318510 pathogenic Cardiovascular phenotype 2020-09-16 criteria provided, single submitter clinical testing 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000468000 SCV000546248 pathogenic Hypertrophic cardiomyopathy 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 719 of the MYH7 protein (p.Arg719Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in families affected with hypertrophic cardiomyopathy (HCM) (PMID: 7848441, 23140321), as well as in multiple unrelated individuals affected with HCM (PMID: 15358028, 15858117, 16199542, 18409188, 21896538, 15519027, 23711808). ClinVar contains an entry for this variant (Variation ID: 14107). Experimental studies have shown that this variant reduces actin filament velocity relative to wildtype (PMID: 10882745). A different missense substitution at this codon (p.Arg719Trp) has been determined to be pathogenic (PMID: 8282798, 20811150, 21310275). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics,University of Leuven RCV000468000 SCV000886786 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000015163 SCV001433302 pathogenic Familial hypertrophic cardiomyopathy 1 2018-12-28 criteria provided, single submitter clinical testing
OMIM RCV000015163 SCV000035420 pathogenic Familial hypertrophic cardiomyopathy 1 1999-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158513 SCV000280312 likely pathogenic not provided 2014-10-08 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.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 ( 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000468000 SCV000804892 likely pathogenic Hypertrophic cardiomyopathy 2016-03-03 no assertion criteria provided clinical testing

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