ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1988G>A (p.Arg663His) (rs371898076)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000158822 SCV000885783 pathogenic not provided 2017-06-22 criteria provided, single submitter clinical testing The MYH7 c.1988G>A; p.Arg663His was initially reported in a large hypertrophic cardiomyopathy pedigree (Gruver 1999) and has since been reported in a large number of HC patients from ethnically diverse populations (Bales 2016, Bashyam 2012, Brito 2012, Chiou 2015, Garcia-Castro 2009, Greber-Platzer 2001, Ingles 2005, Liu 2013, Marsiglia 2013, Miller 2013, Mohiddin 2003, Richard 2003, Song 2005, van Driest 2004, van Rijsingen 2009, Wang 2014, Zou 2013). Other variants affecting the same codon and other nearby codons have also been reported to be pathogenic, suggesting this is a mutational hot-spot (e.g. Curila 2012, Richard 2003, Song 2005, van Driest 2004). Structural studies indicate that this amino acid is located at the myosin-actin interface (Bashyam 2012), and functional cell-based studies demonstrate that the presence of this variant results in calcium dysregulation and elevated intracellular calcium levels (Lan 2013). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.001% (identified on 4 out of 277,188 chromosomes) and is categorized in ClinVar as pathogenic/likely pathogenic (ID 42875). Based on the available information, this variant is classified as pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162333 SCV000212629 pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter research This MYH7 Arg663His variant is a well described HCM causing mutation. Genetic screening in HCM cohorts from various ethnic populations have identified this mutation in multiple unrelated probands (see references). Haplotype analysis has shown that this mutation is not a founder mutation, but rather, this position is a mutational hotspot (Van Driest SL, et al., 2004; Song L, et al., 2005). Mutations at this position which result in different amino acid substitutions have also been detected in HCM patients (Richard P, et al., 2003; Van Driest SL, et al., 2004; Song L, et al., 2005). Familial analysis has shown co-segregation of the variant with disease, however, disease penetrance is incomplete and the phenotype can be variable (Gruver EJ, et al., 1999; Keller DI, et al., 2009). Studies in pediatric HCM cohorts have identified this mutation to be a shared genetic cause of early-onset and adult-onset cardiomyopathy (Morita H, et al., 2008). Functional studies by Lan F, et al. (2013) using patient specific iPSC cardiomyocytes from carriers of this mutation recapitulate disease characteristics including hypertrophy and arrhythmia. To date, we have identified this mutation in 3 index cases with HCM and one possible case of HCM. Based on segregation analysis and the available literature, we classify this variant as "pathogenic".
Ambry Genetics RCV000253409 SCV000320440 pathogenic Cardiovascular phenotype 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Blueprint Genetics RCV000035758 SCV000188797 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000035758 SCV000190423 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Center for Human Genetics,University of Leuven RCV000168409 SCV000886785 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000162333 SCV000693458 pathogenic Familial hypertrophic cardiomyopathy 1 2017-07-17 criteria provided, single submitter clinical testing This heterozygous missense variant in the MYH7 gene was identified in a patient with hypertrophic cardiomyopathy
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000168409 SCV000564419 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1988G>A (p.Arg663His) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:10750581; PMID:11133230; PMID:12707239; PMID:15563892; PMID:16199542; PMID:15358028; AGCMC Sydney ClinVar SCV000212629.1; Invitae ClinVar SCV000219103.7; Partners LMM ClinVar SCV000059409.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >15 affected individuals (PP1_Strong; PMID:10750581; Partners LMM ClinVar SCV000059409.5; SHaRe consortium, PMID: 30297972). This variant was identified in 2/66718 European chromosomes (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). 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
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678721 SCV000804891 pathogenic not specified 2016-12-28 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477919 SCV000536885 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2016-03-24 no assertion criteria provided research
Fulgent Genetics,Fulgent Genetics RCV000762924 SCV000893342 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000158822 SCV000208757 pathogenic not provided 2018-10-29 criteria provided, single submitter clinical testing The R663H pathogenic variant in the MYH7 gene has been reported in several individuals with HCM and has been shown to segregate with disease in multiple affected relatives (Gruver et al., 1999; Greber-Platzer et al., 2001; Richard et al., 2003; Mohiddin et al., 2003; Van Driest et al., 2004; Song et al., 2005; Ingles et al., 2005; Garcia-Castro et al., 2009; van Rijsingen et al., 2009; Brito et al., 2012; Liu et al., 2013; Marsiglia et al., 2013; Miller et al., 2013; Zou et al., 2013; Chiou et al., 2014; Wang et al., 2014; Bales et al., 2016). In addition, the R663H variant has been classified in ClinVar as a pathogenic variant by other clinical laboratories (ClinVar SCV000219103.4, SCV000059409.4, SCV000188797.3, SCV000280309.1; Landrum et al., 2016), and has been observed in multiple unrelated individuals referred for HCM genetic testing at GeneDx. The R663H pathogenic variant was initially reported by Gruver et al. (1999) in one large family where it co-segregated with disease in 16 family members with modest left ventricular hypertrophy that progressively increased with age. Individuals harboring the R663H variant had a markedly higher prevalence of atrial fibrillation when compared to other HCM patients (genotypes unknown), while survival of individuals with R663H remained near normal (Gruver et al., 1999).The R663 residue, located in the actin binding region at part of the actin–myosin interface (Bashyam et al., 2012), is considered a hot spot" for pathogenic variants (Van Driest et al., 2004; Song et al., 2005). Variants at this residue may result in conformational changes at the actin binding region (Bashyam et al., 2012). Missense variants in nearby residues (L658V, M659T, M659I, T660N) and different missense variants affecting the same residue (R663S, R663C) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. A functional study by Lan et al. (2013) used patient derived cells to demonstrate that R663H is strongly implicated in the dysregulation of calcium ion cycling, causing elevation of calcium ions which can induce both cellular hypertrophy and contractile arrhythmia. Furthermore, R663H was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, R663H in the MYH7 gene is interpreted as a pathogenic variant."
Integrated Genetics/Laboratory Corporation of America RCV000253409 SCV000696339 pathogenic Cardiovascular phenotype 2016-06-08 criteria provided, single submitter clinical testing Variant summary: The MYH7 c.1988G>A (p.Arg663His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, and several functional assays indicate that this variant is functionally defective (Lan_CSC_2013). This variant was found in 2/121338 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0010005). It has been identified in numerous HCM patients in the literature, and has been shown to co-segregate with disease (Gruver_AJC_1999). Additionally, multiple clinical labs have classified the variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000168409 SCV000219103 pathogenic Hypertrophic cardiomyopathy 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 663 of the MYH7 protein (p.Arg663His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371898076, ExAC 0.003%). This sequence change has been reported in the literature in numerous unrelated individuals with hypertrophic cardiomyopathy (PMID: 12707239, 12820698, 15358028, 15563892, 16199542, 23283745, 23396983, 26914223), and shows segregation with the phenotype in several families (PMID: 10750581, 11133230, 23290139). ClinVar contains an entry for this variant (Variation ID: 42875). A different missense substitution at this codon (p.Arg663Cys) has been determined to be pathogenic (PMID: 15358028, 15563892, 23283745, 15858117, 22112859, 20800588, 23233322, 18383048, 23690394). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in multiple affected individuals and has been shown to segregate with disease in several families. For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168409 SCV000059409 pathogenic Hypertrophic cardiomyopathy 2014-03-14 criteria provided, single submitter clinical testing The p.Arg663His variant in MYH7 has previously been reported in >40 individuals with HCM and was shown to segregate with disease in >25 affected relatives (Gruv er 1999, Greber-Platzer 2001, Mohiddin 2003, Richard 2003, Van Driest 2004, Song 2005, Ingles 2005, Zou 2013, Lan 2013, LMM unpublished data). This variant has been identified in 0.01% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Functional studies showed that this variant impacts protein function (Lan 2013); however, this in vitro assay may not accurately represent biological function. This variant meets our criteria to be classified as pathogenic (http://www.partners.org/personaliz edmedicine/LMM) based upon frequency in cases relative to the general population and extensive segregation with disease.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000162333 SCV000256124 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035758 SCV000748019 pathogenic Primary familial hypertrophic cardiomyopathy 2017-02-15 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158822 SCV000280309 pathogenic not provided 2014-02-06 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.Arg663His (c.1988G>A) Based on the strong case data, absence in controls, and presence of other pathogenic variants at the same codon, we consider this variant very likely disease causing. Per their ClinVar submission LMM considers it pathogenic (SCV000059409). The variant has been seen in at least 23 unrelated cases of HCM, likely more, with very strong segregation data in one family (Greber-Platzer et al 2001 1 case, Gruver et al 1999 1 family, Richard et al 2003 2 cases, van Driest et al 2004 8 cases, Mohiddin et al 2003 3 cases, Xie et al 2004 ?, Song et al 2005 4 cases). Gruver et al (1999) reported this mutation in a large family, segregating with HCM in 16 individuals. There are likely additional published cases; we have not updated our review of the literature for a few years. In our center we have seen the variant in four patients: an African-American woman with HCM and two of her affected family members (described in Lan et al 2012); a Caucasian male diagnosed with HCM in his teens with a father who also has HCM; a woman diagnosed with HCM at 41 years of age; a Japanese woman diagnosed with HCM at 25yo who underwent heart transplant at 56yo. This third patient also carries p.Val1360Ile (we classify as a VUS) on the same allele and p. Ala26Val (we classify as a VUS) on the other allele. Her affected brother carries the allele with p.Arg663His and p.Val1360Ile but not the allele with p.Ala26Val. Her affected father, paternal uncle, paternal cousin, and paternal aunt were not available for genetic testing. Other pathogenic variants have been reported at this codon: p.Arg663Cys and p.Arg663Ser. Van Driest et al (2004) described codon 663 as a ‘hotspot’ with 9 out of 58 (15%) patients with MYH7 variants in that study having a variant involving codon 663. PolyPhen2 predicts the variant to be possibly damaging and mutationtaster predicts it to be disease causing. The variant has been seen in 1 of 6873 publicly available general population samples and published controls. This variant has been reported as absent in 100 (Richard et al 2006), 200 (van Driest et al 2004) and 120 (Song et al 2005) control individuals, for a total of 420 ethnically diverse controls. The variant was recently reported online in 1 of 4250 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of May 24th, 2013). The phenotype of that individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other very likely disease causing sarcomere variants have been seen in published controls (Pan et al 2012).

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