rs121913630
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 17P and 1B. BP2PS4PP1_StrongPP3PM6PM1PM5PM2
This summary comes from the ClinGen Evidence Repository: The c.2167C>T (p.Arg723Cys) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1430197; PMID:27532257; PMID:9829907; PMID:16199542; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). Five of these probands carried additional variants in sarcomere genes (BP2; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:1430197). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:9829907; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). This variant was identified in 2/66738 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). 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.2167C>G p.Arg723Gly - ClinVar Variation ID 42885). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. The benign evidence code BP2 was not considered to be in conflict with this conclusion given that presence of a second variant can be seen in individuals with cardiomyopathy and may contribute to the severity of disease. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PM6; PP3; BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011851/MONDO:0005045/002
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
MYH7
ENST00000355349.4 missense
ENST00000355349.4 missense
Scores
11
6
3
Clinical Significance
Conservation
PhyloP100: 2.03
Genes affected
MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PM6
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
BP2
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH7 | NM_000257.4 | c.2167C>T | p.Arg723Cys | missense_variant | 20/40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.2167C>T | p.Arg723Cys | missense_variant | 19/39 | NP_001393933.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH7 | ENST00000355349.4 | c.2167C>T | p.Arg723Cys | missense_variant | 20/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251214Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135772
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727136
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GnomAD4 genome 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2022 | 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: 25351510, 22957257, 16199542, 20359594, 21835320, 21310275, 25524337, 12707239, 26507537, 25935763, 24510615, 27247418, 27532257, 23074333, 9829907, 29300372, 31006259, 30624779, 31447099, 33662488, 33673806, 32880476, 34352619, 34135346, 32894683, 1430197) - |
| Pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 16, 2012 | 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.Arg723Cys (c.2167C>T) in the MYH7 gene. This variant has been seen in at least 6 unrelated families with HCM (not including in our cohort), with strong segregation data in one family. Watkins et al (1992) described the variant in a proband with HCM. Tesson et al (1998) reported this variant with HCM. The variant segregated with HCM in one family; the variant was found in 11 members of a family, 6 of those individuals had HCM. This family had no incidence of early or sudden cardiac death. Richard et al (2003) reported the variant in a patient with HCM who also carried p.Val39Met in MYH7. Two individuals with just p.Arg723Cys had HCM, while individuals with both variants had more severe hypertrophy (on average) (likely the same case as reported in Charron et al 1997). Ingles et al (2005) reported the variant in a patient with HCM from their Australian cohort. Girolami et al (2010) reported a patient with HCM who carried p.Arg723Cys in trans with p.Glu1455Ter as well as p.Glu165Asp in MYBPC3 (same patient reported in Olivotto et al 2011). Maron et al (2012) include an individual with this variant in a paper on myocardial crypts in HCM. That patient is listed as one who does not have a diagnosis of HCM yet but is predisposed and has a family history. No information is provided about family members with HCM who have the variant. LMM submitted their classification of the variant (pathogenic) to ClinVar with a total of 9 families, citing 5 in the literature, which suggests they may have seen the variant in 4 additional families (http://www.ncbi.nlm.nih.gov/clinvar/RCV000035772/#evidence). Additionally other variants in the same codon (p.Arg723His, p.Arg723Gly) as well as neighboring codons (p.Arg721Lys) have been reported in association with HCM in published literature. Arginine is highly conserved at this position across species. The variant has not been seen in a total of ~6740 publicly available general population samples and published controls. There is no variation at codon 723 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6300 Caucasian and African American individuals (as of 9 December 2013). This variant was not observed in 440 published controls: 90 (Watkins et al 1992), 100 (Tesson et al 1998), 100 (Richard et al 2003), 150 (Ingles et al 2005). The variant is listed in dbSNP (rs121913630), however the submitted data is from LMM and OMIM and thus relates to its presence in affected individuals. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 08, 2020 | - - |
Hypertrophic cardiomyopathy 1 Pathogenic:5
| Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | - | This MYH7 Arg723Cys variant has previously been identified in a small number of unrelated cases with HCM (see references). The variant was first reported as a de novo mutation (Watkins H, et al., 1992). Segregation analysis has shown this variant to segregate with disease with incomplete penetrance (Tesson F, et al., 1998; Richard P, et al., 2003; Girolami F, et al., 2010). Interestingly, Tesson F (1998) described monozygotic twins who carry this mutation where only one twin had left ventricular hypertrophy. We identified this mutation in 2 unrelated families (Ingles J, et al., 2005) and have shown this variant to segregate with disease (unpublished data). Based on existing reports and our data, we classify this variant as "pathogenic". - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Oct 23, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 16, 2023 | - - |
Hypertrophic cardiomyopathy Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 28, 2024 | This missense variant replaces arginine with cysteine at codon 723 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies using human induced pluripotent stem cells have shown that this variant causes a cellular hypertrophy phenotype in cardiomyocytes (PMID: 35784482). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25935763, 29300372, 29710196, 29875424, 31245010, 32481709, 33495596, 33495597, 33673806, 35384713, 36843271), in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087), and in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been reported to arise de novo in two individuals affected with hypertrophic cardiomyopathy (PMID: 1430197, 31245010). This variant has also been reported in compound heterozygous state with an MYH7 truncation variant in one individual affected with severe hypertrophic cardiomyopathy (PMID: 20359594). A few family member carriers of this variant have been reported to be unaffected, suggesting a reduced penetrance for this variant (PMID: 9829907, 20359594, 25935763); this variant has also been reported in one healthy older adult (PMID: 34135346). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 36843271). A different variant affecting the same codon, p.Arg723Gly, is considered to be disease-causing (ClinVar variation ID: 42885), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Dec 15, 2016 | The c.2167C>T (p.Arg723Cys) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1430197; PMID:27532257; PMID:9829907; PMID:16199542; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). Five of these probands carried additional variants in sarcomere genes (BP2; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:1430197). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:9829907; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). This variant was identified in 2/66738 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). 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.2167C>G p.Arg723Gly - ClinVar Variation ID 42885). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. The benign evidence code BP2 was not considered to be in conflict with this conclusion given that presence of a second variant can be seen in individuals with cardiomyopathy and may contribute to the severity of disease. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PM6; PP3; BP2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 723 of the MYH7 protein (p.Arg723Cys). This variant is present in population databases (rs121913630, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or arrhythmogenic right ventricular cardiomyopathy (PMID: 1430197, 9829907, 12117842, 16199542, 25935763, 29709087). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14095). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 30, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2023 | This missense variant replaces arginine with cysteine at codon 723 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies using human induced pluripotent stem cells have shown that this variant causes a cellular hypertrophy phenotype in cardiomyocytes (PMID: 35784482). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25935763, 29300372, 29710196, 29875424, 31245010, 32481709, 33495596, 33495597, 33673806, 35384713, 36843271), in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087), and in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been reported to arise de novo in two individuals affected with hypertrophic cardiomyopathy (PMID: 1430197, 31245010). This variant has also been reported in compound heterozygous state with an MYH7 truncation variant in one individual affected with severe hypertrophic cardiomyopathy (PMID: 20359594). A few family member carriers of this variant have been reported to be unaffected, suggesting a reduced penetrance for this variant (PMID: 9829907, 20359594, 25935763); this variant has also been reported in one healthy older adult (PMID: 34135346). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 36843271). A different variant affecting the same codon, p.Arg723Gly, is considered to be disease-causing (ClinVar variation ID: 42885), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:2
| Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Dec 31, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2022 | Variant summary: MYH7 c.2167C>T (p.Arg723Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 252214 control chromosomes. c.2167C>T has been widely reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (example, Girolami_2010, Ingles_2005, Jouven_2002, Olivotto_2008, Richard_2003, Watkins_1992). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2022 | The p.R723C pathogenic mutation (also known as c.2167C>T) is located in coding exon 18 in the MYH7 gene. This variant results from a C to T substitution at nucleotide position 2167. The arginine at codon 723 is replaced by cysteine, an amino acid with highly 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 variant has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in several families (Tesson F et al 1998. Hum Mutat. 1998;12(6):385-392; Richard P et al. Circulation. 2003;107(17):2227-2232; Girolami F et al. J Am Coll Cardiol. 2010;55(4):1444-53; Walsh R et al. Genet. Med., 2017 02;19:192-203; Kelly MA et al. Genet. Med., 2018 03;20:351-359). In addition, this variant was described as de novo in a patient with features of HCM (Watkins H et al. J Clin Invest. 1992;90(5):1666-1171). Another alteration at the same codon, p.R723G (c.2167C>G), has also been reported in association with HCM (Yang JH et al. Chin Med J (Engl). 2006; 119(21):1785-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Name
Calibrated prediction
Score
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AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at A728 (P = 0);
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MPC
ClinPred
D
GERP RS
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gMVP
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at