rs371898076
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4PM1PM2PP1_Strong
This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011552/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000395 AC: 6AN: 151758Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251480Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727228
GnomAD4 genome 0.0000395 AC: 6AN: 151758Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 74070
ClinVar
Submissions by phenotype
not provided Pathogenic:10
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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The MYH7 c.1988G>A; p.Arg663His variant (rs371898076) was initially reported in a large hypertrophic cardiomyopathy (HC) 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% (4/282,842 alleles) and is categorized in ClinVar as pathogenic/likely pathogenic (Variation ID: 42875). Based on the available information, this variant is classified as pathogenic. References: Bales ND et al. Comprehensive Versus Targeted Genetic Testing in Children with Hypertrophic Cardiomyopathy. Pediatr Cardiol. 2016 Jun;37(5):845-51. Bashyam MD et al. A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. Mol Cell Biochem. 2012 Jan;360(1-2):373-82. Brito D et al. Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population. Rev Port Cardiol. 2012 Sep;31(9):577-87. Doi: 10.1016/j.repc.2011.12.020. Chiou KR et al. Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan. J Cardiol. 2015 Mar;65(3):250-6. Curila K et al. Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy. Acta Cardiol. 2012 Feb;67(1):23-9. Garcia-Castro M et al. Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy. Rev Esp Cardiol. 2009 Jan;62(1):48-56. Greber-Platzer S et al. Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children. J Mol Cell Cardiol. 2001 Jan;33(1):141-8. Gruver EJ et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol. 1999 Jun 17;83(12A):13H-18H. Ingles J et al. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005 Oct;42(10):e59. Lan F et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013 Jan 3;12(1):101-13. Liu W et al. Mutation spectrum in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy. Am J Cardiol. 2013 Aug 15;112(4):585-9. Marsiglia JD et al. Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. Am Heart J. 2013 Oct;166(4):775-82. Miller EM et al. Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families. J Genet Couns. 2013 Apr;22(2):258-67. Mohiddin SA et al. Utility of genetic screening in hypertrophic cardiomyopathy: prevalence and significance of novel and double (homozygous and heterozygous) beta-myosin mutations. Genet Test. 2003 Spring;7(1):21-7. Richard P et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. Song L et al. Mutations profile in Chinese patients with hypertrophic cardiomyopathy. Clin Chim Acta. 2005 Jan;351(1-2):209-16. van Driest SL et al. Comprehensive analysis of -
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; Functional studies using patient derived cells demonstrated p.(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 (Lan et al., 2013); This variant is associated with the following publications: (PMID: 23283745, 25637381, 23299917, 15563892, 27247418, 23396983, 11133230, 16199542, 28718902, 28573431, 15358028, 17125710, 15858117, 20800588, 23233322, 30984009, 24566549, 20087448, 24093860, 22857948, 18403758, 21959974, 19150014, 23054336, 23711808, 26936621, 12820698, 10750581, 28166811, 26914223, 21310275, 27532257, 25132132, 23690394, 17560888, 27600940, 27639548, 18533079, 29300372, 29121657, 29907873, 30217213, 12707239, 22112859, 31006259, 30685992, 30324321, 31931472, 31513939, 31737537, 32284968, 31447099, 33673806, 33586461, 32746448, 33407484, 32894683, 25086479, 23290139, 34137518, 33658040, 33906374, 24704860) -
PP1_strong, PM1, PM2, PS3_moderate, PS4 -
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Hypertrophic cardiomyopathy Pathogenic:7
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. -
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 -
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This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 663 of the MYH7 protein (p.Arg663His). This variant is present in population databases (rs371898076, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10750581, 11133230, 12707239, 12820698, 15358028, 15563892, 16199542, 23283745, 23290139, 23396983, 26914223). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42875). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg663 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 15563892, 15858117, 18383048, 20800588, 22112859, 23233322, 23283745, 23690394). 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. -
This missense variant replaces arginine with histidine at codon 663 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies shown that this variant affects MYH7 protein function and causes arrhythmias and abnormal Ca2+ transients (PMID: 23290139). This variant has been reported in over 30 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16199542, 18403758, 23396983, 24093860, 24793961, 25086479, 26914223, 27532257, 29907873, 31513939, 31737537, 31931472) and has been shown to segregate with disease in multiple affected individuals across several families (PMID: 10750581, 11133230, 23290139). This variant is thought to cause later-onset hypertrophic cardiomyopathy with mild clinical symptoms (PMID: 11133230). This variant has been identified in 4/282842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg663Cys, is considered to be disease-causing (ClinVar variation ID: 42874), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
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Hypertrophic cardiomyopathy 1 Pathogenic:6
PS4, PM1, PM5, PP5, PS3 -
This c.1988G>A (p.Arg663His) variant in the MYH7 gene has been reported in multiple unrelated individiuals affected with hypertrophic cardiomyopathy (PMID 10750581, 11133230, 15358028, 15563892, 21959974, 22112859, 23233322, 23290139) and segregates with disease in two families (PMID 10750581, 23290139). This variant is absent in the general population. This variant is located in myosin head domain of the MYH7 gene where multiple pathogenic variants have been identified. Therefore, this c.1988G>A (p.Arg663His) variant in the MYH7 gene is classified as pathogenic. -
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". -
This heterozygous missense variant in the MYH7 gene was identified in a patient with hypertrophic cardiomyopathy -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Predicted Consequence/Location: Missense variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [REVEL: 0.58 (damaging >=0.6, benign <0.4), 3Cnet: 0.07 (damaging >=0.6, benign <0.15), Splice AI: 0.04 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A4 related disorder (ClinVar ID: VCV000334704 /PMID: 28476686 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28476686, 30968591, 32332277, 32703181). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Primary familial hypertrophic cardiomyopathy Pathogenic:3
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Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:2
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PS4+PP1_Strong+PM1+PM5+PP3+PM2_Supporting -
Cardiovascular phenotype Pathogenic:2
The p.R663H pathogenic mutation (also known as c.1988G>A), located in coding exon 16 of the MYH7 gene, results from a G to A substitution at nucleotide position 1988. The arginine at codon 663 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and co-segregated with disease in multiple families (Gruver EJ et al. Am J Cardiol. 1999;83(12A):13H-18H; Greber-Platzer S et al. J Mol Cell Cardiol. 2001;33(1):141-8; Ingles J et al. J Med Genet. 2005;42(10):e59; Keller DI et al. Int J Cardiol. 2009;134(3):e87-93; Bos JM et al. Mayo Clin Proc. 2014;89(6):727-37; Bales ND et al. Pediatr Cardiol, 2016 Jun;37:845-51). A study of induced pluripotent stem cell cardiomyocytes derived from individuals with this alteration reported that disease characteristics and abnormal calcium handling were demonstrated at the cellular-level (Lan F et al. Cell Stem Cell. 2013;12(1):101-13). In addition, two other alterations at the same codon, p.R633S (c.1987C>A) and p.R663C (c.1987C>T), have also been reported in association with HCM (Richard P et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Song L et al. Clin Chim Acta. 2005;351(1-2):209-16). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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. -
not specified Pathogenic:1
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Cardiomyopathy Pathogenic:1
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Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1
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MYH7-related disorder Pathogenic:1
The MYH7 c.1988G>A variant is predicted to result in the amino acid substitution p.Arg663His. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been observed to segregate with HCM in multiple families (Gruver et al. 1999. PubMed ID: 10750581; Richard et al. 2003. PubMed ID: 12707239; Van Driest et al. 2004. PubMed ID: 15358028; Lan et al. 2013. PubMed ID: 23290139). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. The ClinGen Cardiomyopathy Variant Curation Expert Panel interprets this variant as pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/42875/). Alternate nucleotide changes affecting the same amino acid (p.Arg663Ser and p.Arg663Cys) have also been reported to be associated with HCM (Human Gene Mutation Database, HGMD). The c.1988G>A (p.ArgHis) variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at