rs121913625
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.1357C>T(p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453H) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
15
4
1
Clinical Significance
Conservation
PhyloP100: 1.75
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 15 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23429004-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 14-23429005-G-A is Pathogenic according to our data. Variant chr14-23429005-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14089.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429005-G-A is described in Lovd as [Pathogenic]. Variant chr14-23429005-G-A is described in Lovd as [Pathogenic]. Variant chr14-23429005-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH7 | NM_000257.4 | c.1357C>T | p.Arg453Cys | missense_variant | 14/40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.1357C>T | p.Arg453Cys | missense_variant | 13/39 | NP_001393933.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH7 | ENST00000355349.4 | c.1357C>T | p.Arg453Cys | missense_variant | 14/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727246
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GnomAD4 genome 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:24
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 28, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 31, 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.Arg453Cys (c.1357 C>T) in MYH7 (NM_000257.2) Given the strong case data, segregation data, and mouse model, we consider this variant very likely disease causing. The variant has been seen in over 15 unrelated cases of HCM with strong segregation data. Watkins et al (1992) reported p.Arg453Cys in two families with HCM with a Lod score of 4.4 in one family and a Lod score of 3.9 in the other. Unfortunately details on the number of affected individuals with the variant in each family was not reported. The same authors then reported a third family with HCM and this variant (Watkins et al 1993). In that paper they demonstrated that the variant occurred on three distinct haplotypes in these three families. Ko et al (1996) reported a Chinese kindred with 8 individuals with HCM and p.Arg453Cys. Forissier et al (2000) reported two siblings with HCM and p.Arg453Cys. Interestingly, this was the first reported case of germline mosaicism in HCM. In a cohort of Australian families with HCM, Greber-Platzer et al (2001) reported one family with two affected individuals with p.Arg453Cys. Ackerman et al (2002) reported a child with HCM and p.Arg453Cys. Richard et al (2003) observed p.Arg453Cys in two unrelated individuals with HCM. In a Spanish cohort, Garcia-Castro et al (2003) observed the variant in one case of HCM. Nanni et al (2003) also observed the variant in one individual with HCM. Woo et al (2003) reported two individuals with this variant and HCM (unclear if they are related to each other). Perrot et al (2005) observed the variant in one individual with HCM. Yu et al (2005) observed the variant in one patient with HCM. The variant has been seen with another variant in at least one case (van Driest et al 2004). The patient also carried p.Gln191del in TNNT2. There are multiple additional reports on the variant that I did not review (including, but not limited to Kubo et al 2007, Solomon et al 1993, Bos et al 2014, Kassem et al 2013). We have seen the variant in one other patient with HCM in our center. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 453 is conserved across species, as are neighboring variants. This is a non-conservative amino acid change. There are other variants at this codon: p.Arg453Leu, which we consider a variant of uncertain significance; p.Arg453His, which we consider likely disease causing; p.Arg453Ser, which we have not reviewed. Variants at nearby codons have been reported in association with cardiomyopathy (p.Lys450Glu, p.Lys450Thr). The Seidman group has developed a mouse model with p.Arg453Cys that recapitulates an HCM phenotype (Palmer et al 2004, Debold et al 2007). Some authors have suggested that this variant is associated with a particularly severe phenotype. However, many such assertions made in early studies of HCM genetics were later called in to question when milder cases with such "severe" variants were reported and vice versa (ex. van Driest et al 2002). It is certainly possible that this variant causes a more severe phenotype, however further studies are needed to assess that. In addition, even with such a correlation, there may still be some variability among patients with this variant. In total the variant has not been seen in ~7002 published controls and publicly available population datasets. There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 15th, 2014). The variant was not observed in published controls: 100 (Richard et al 2003), 100 (Garcia-Castro et al 2003), 100 (Nanni et al 200 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2022 | Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as reduced ATPase activity and enhanced calcium sensitivity result in a hyper-contractile state of the cardiac muscle (Palmer et al., 2004; Debold et al., 2007; Tajsharghi et al., 2008; Sommese et al., 2013; Bloemink et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564414.4; ClinVar); This variant is associated with the following publications: (PMID: 17351073, 17495353, 15851227, 17599605, 16715312, 18175163, 12707239, 29029073, 1552912, 23283745, 12881443, 15358028, 23349452, 12951062, 15856146, 18365899, 15001446, 23798412, 10662815, 11133230, 27247418, 21310275, 27373729, 27532257, 9541100, 1739523, 24111713, 29300372, 8655135, 12975413, 29907873, 31513939, 32013205, 32283115, 24344137, 31006259, 33673806, 33586461) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hypertrophic cardiomyopathy Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 453 of the MYH7 protein (p.Arg453Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1552912, 1739523, 1975599, 8250038, 11133230, 12975413, 17599605, 20031618, 23283745, 24093860, 24111713). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14089). 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: 15001446, 17351073, 23798412, 24344137). This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15858117). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 06, 2012 | The p.Arg453Cys variant in MYH7 has been identified in >20 families with HCM or RCM, segregated with disease in >10 affected members of several families, and oc curred de novo in 2 children with HCM (Ko 1996, Forissier 2000, Greber-Platzer 2 001, Ackerman 2002, Garcia-Castro 2003, Nanni 2003, Woo 2003, Van Driest 2004, P errot 2005, LMM unpublished data). It was absent from large population studies ( http://evs.gs.washington.edu/EVS). In summary, this variant meets our criteria t o be classified as pathogenic for HCM in an autosomal dominant manner (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies, de novo occurrences, and absence from controls. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 10, 2016 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Dec 15, 2016 | The c.1357C>T (p.Arg453Cys) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:8655135; PMID:10662815; PMID:11133230; PMID:12084606; PMID:12881443; PMID:17599605; PMID:23349452; PMID: 27532257; Partners LMM ClinVar SCV000059368.5; AGCMC Sydney ClinVar SCV000212633.1; SHaRe consortium, PMID: 30297972). This variant has been identified as an unconfirmed de novo occurrence in 3 individuals with hypertrophic cardiomyopathy (PM6_Strong; Partners LMM ClinVar SCV000059368.5). This variant segregated with disease in >10 affected individuals (PP1_Strong: PMID:8655135; PMID:10662815; PMID:11133230; Partners LMM ClinVar SCV000059368.5; AGCMC Sydney ClinVar SCV000212633.1). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (PS2; PMID:23798412; PMID:24344137). 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). 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): PS3; PS4; PM6_Strong; PP1_ Strong; PM1; PM2; PP3 - |
Hypertrophic cardiomyopathy 1 Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1996 | - - |
| Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | - | This MYH7 Arg453Cys mutation is well described in the literature. The mutation has been identified in multiple unrelated individuals and families with HCM (see references). This mutation is not a founder mutation but rather, occurs in a well known hotspot region of the MYH7 gene and has an independent origin is each family (Watkins H, et al., 1993). Additionally, a different mutation affecting the same protein position (Arg453Ser) has been identified to also cause HCM (Frazier A, et al., 2008). Interestingly, this MYH7 Arg453Cys mutation has been identified as the cause of disease in the first HCM family described by Teare in 1958 (Watkins H, et al., 1992). This mutation is inherited as an autosomal trait with high penetrance, has been shown to cosegregate with disease, and is associated with unfavourable prognoses in multiple families (Solomon SD, et al., 1990; Watkins H, et al., 1992 & 1993; Ko YL, et al., 1996; Greber-Platzer S, et al., 2001). We have identified this mutation in one HCM family from our cohort. Based on the available literature, segregation analysis, and absence in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), we classify this variant as "pathogenic". - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 27, 2023 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 12, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University | Jun 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 21, 2017 | - - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 05, 2019 | - - |
Primary dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Loeys Lab, Universiteit Antwerpen | Feb 26, 2021 | This sequence change results in a missense variant in the MYH7 gene (p.(Arg453Cys)). (PP2; based on GnomAd constraint matrix). This variant is absent from population databases such as GnomAD (PM2) . This variant has been described in literature in several unrelated individuals. Was found de novo in two children with HCM and showed coseggregation in >20 families (>10 individuals).(PMID:8655135; PMID:10662815; PMID: 11133230; PMID:12084606; PMID:12881443; PMID:12951062; PMID:12975413; PMID:15358028) (PP1; PS2). Functional data of homozygous and hetrozygous mice show that the variant significantly decreases the maximum rate if ATP turnover, resulting in a large increase in the maximal force-generating capacity (PMID: 17351073; PMID:15001446). Similar findings were present in a constructed human MYH7 protein (PMID: 23798412 )(PS3). The variant affects a highly conserved amino acid and another variant that disrupt this amino acid has been reported as pathogenic p.Arg453His (PM5). The variant is located in a region of the MYH7 known as a mutational-hotspot (PM1). Prediction programs all classify this variant as pathogenic (AlignGVGD: C65, pathogenic; Polyphen-2 HumDiv: probably damaging; Polyphen-2 HumVar: probably damaging;; SIFT:deleterious; MutationTaster: disease causing). (PP3). We identified this variant in a patients with familial DCM. In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS2,PS3, PM1, PM2,PM5,PP1,PP3). - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2021 | The p.R453C pathogenic mutation (also known as c.1357C>T), located in coding exon 12 of the MYH7 gene, results from a C to T substitution at nucleotide position 1357. The arginine at codon 453 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 alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) (Ackerman MJ et al. J Am Coll Cardiol. 2002;39(12): 2042-8; García-Castro M et al. Clin Chem. 2003;49(8):1279-85; Nanni L et al. Biochem Biophys Res Commun. 2003;309(2):391-8; Woo A et al. Heart. 2003;89(10):1179-85; Walsh R et al. Genet. Med., 2017 Feb;19:192-203), has been reported to segregate with disease in families (Watkins H et al. N Engl J Med. 1992;326(17):1108-14; Watkins H et al. Am J Hum Genet. 1993;53(6):1180-5; Ko YL et al. Hum Genet. 1996;97(5):585-90; Forissier JF et al. J Med Genet. 2000;37(2):132-4; Greber-Platzer S et al. J Mol Cell Cardiol. 2001;33(1):141-8), and has been reported as occurring de novo in an individual with HCM with restrictive features (Franaszczyk M et al. J Clin Med. 2020 Jan;9(2)). In addition, studies of mouse models harboring this alteration recapitulated HCM phenotype (Palmer BM et al. Am J Physiol Heart Circ Physiol. 2004;287(1):H91-9. Debold EP et al. Am J Physiol Heart Circ Physiol. 2007;293(1):H284-91). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
MYH7-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2023 | The MYH7 c.1357C>T variant is predicted to result in the amino acid substitution p.Arg453Cys. This variant was reported in more than twenty unrelated individuals with hypertrophic cardiomyopathy (Watkins et al. 1992. PubMed ID: 1552912; Tables S1A and S1B, Walsh et al. 2017. PubMed ID: 27532257; Franaszczyk et al. 2020. PubMed ID: 32013205). Functional studies support the pathogenicity of this variant (Debold et al. 2007. PubMed ID: 17351073; Sommese et al. 2013. PubMed ID: 23798412). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic by ClinGen Cardiomyopathy Variant Curation Expert Panel (www.ncbi.nlm.nih.gov/clinvar/variation/14089/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at P452 (P = 1e-04);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at