rs397516127
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.1987C>T(p.Arg663Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,864 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R663H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
15
4
1
Clinical Significance
Conservation
PhyloP100: 2.05
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 19 ACMG points.
PM1
In a region_of_interest Actin-binding (size 22) in uniprot entity MYH7_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000257.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23426833-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, 0.966
PP5
Variant 14-23426834-G-A is Pathogenic according to our data. Variant chr14-23426834-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23426834-G-A is described in Lovd as [Pathogenic]. Variant chr14-23426834-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.1987C>T | p.Arg663Cys | missense_variant | 18/40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.1987C>T | p.Arg663Cys | missense_variant | 17/39 | NP_001393933.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH7 | ENST00000355349.4 | c.1987C>T | p.Arg663Cys | missense_variant | 18/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 exome
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3
AN:
1461864
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Cov.:
32
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2
AN XY:
727234
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Nov 04, 2016 | The following genes were evaluated for sequence changes and exonic deletions/duplications (ACTC1, ACTN2, BAG3, CAV3, CSRP3, DES, ELAC2, FHL1, GLA, LAMP2, MTO1, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTR, VCL). The p.Arg663Cys (c.1987C>T) variant in the MYH7 gene was found. Given the strong case data, absence in controls, and presence of other pathogenic variants at the same codon, we classify this variant as very likely disease-causing (aka pathogenic). We feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We re-reviewed the variant November 4th, 2016. This variant is present in ClinVar. It is classified as likely pathogenic by 3 labs (LMM, GeneDx and the CHEO) and pathogenic by Blueprint. Case Data: The Arg663Cys variant has been previously reported in at least 19 presumably unrelated individuals with HCM. It segregates with at least 4 affected relatives (SHaRe) and possibly an additional 7 (Song et al. 2005). Van Driest 2004: This variant was present in 1 out of 389 patients with HCM from their Mayo cohort. The variant was absent in 200 control individuals Song 2005: This variant was present in 1 out of 100 unrelated Chinese patients with HCM. There may be strong published segregation data, although the paper is a bit unclear about how to interpret this data: they found Arg663Cys in one proband, but in Table 3 they describe 8 affected individuals showing 100% penetrance of Arg663Cys. They do not specify that all 8 individuals are from one family; however, they do indicate that individuals with this variant have a family history of sudden cardiac death and that two other family members died of HCM at a young age. This variant was absent in 120 control individuals. This report is presumably redundant with Zou et al 2013. Of note, Zou et al report that the patient had an additional variant in MYH7, p.Gln892Lys (Q892K). The Q892K variant is not reported in the literature, has not been seen in gnomAD and is predicted to alter a splice site. Yu 2005: This variant was present in 2 out of 150 unrelated Australian patients with HCM. The variant was absent in 100 ethnically-matched controls. Olivotto 2008: This variant was present in 1 out of 61 patients with HCM for their Florence cohort. This patient was a 45-year old male with a maximum LV wall thickness of 27mm. This variant was absent from 150 adult ethnically-matched controls. This may be redundant with the report by Coppini et al since both include patients from the Florence cohort. Hirota 2010: This variant was present in at least 1 out of 93 probands with HCM. It is unclear how many probands had this variant. Witjas-Paalberends 2013: This variant was present in 1 out of 43 probands with HCM. It is unclear where these patients were recruited from, however it is possible there is overlap with Mook et al 2013 as both studies have multiple authors from Amsterdam. Mook 2013: This variant was found in a patient with HCM from a clinical genetic testing cohort in amsterdam. Kassem 2013: This variant was found in 1 of 199 unrelated HCM patients from Egypt. The variant was not present in 100 healthy controls. Zhao et al 2016: This variant was found in 1 out of 8 patients with HCM from their Chinese cohort. This variant was absent from 100 control subjects. Based on authors and institutions this appears to be a distinct case from Song et al and Zou et al. In the SHaRe consortium the variant has been seen in the following unrelated HCM patients: three from the Yale cohort, three from the Michigan cohort, five from Florence, and one from Brigham and Women’s. Some of these cases overlap with Coppini et al, Olivotto et al, and the cases from the genetic testing laboratories. If we do not count laboratory data, then we can take 11 unique cases from the SHaRe dataset. There are also four affected relatives from various SHaRe sites who carry the variant. Other variants have be - |
| 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 | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21835320, 23690394, 27532257, 20800588, 30847666, 18383048, 23674513, 25714468, 25228707, 25351510, 23785128, 27247418, 15858117, 20350521, 23283745, 23233322, 25524337, 21799269, 15563892, 28606303, 27590665, 29497013, 29030401, 28193612, 29661763, 29743414, 27082122, 21310275, 22112859, 30775854, 32344918, 15358028, 32894683, 35653365, 35626289, 33673806, 32830170, 29300372) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | MYH7: PS4, PM2, PM5, PP2, PP3 - |
Hypertrophic cardiomyopathy Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 16, 2023 | The MYH7 c.1987C>T variant is classified as Pathogenic (PS4, PM1, PM2, PP1_Moderate, PP3.) The MYH7 c.1987C>T variant is a single nucleotide change in exon 18/40 of the MYH7 gene, which is predicted to change the amino acid arginine at position 663 in the protein, to cysteine. This amino acid is within the conserved functional domain of the MYH7 protein where variation is expected to be disease causing (PM1). The variant has been reported in excess of 20 probands with a clinical presentation of Hypertrophic Cardiomyopathy (PMID#15358028, 33673806, 32344918, 30775854, 32894683, 35626289) (PS4) and is absent from population databases (PM2). This variant has been reported to segregate with disease (PMID #15563892, our cohort and SHaRE) (PP1_moderate). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397516127) is reported as disease causing in the HGMD database (CM973126) and is reported as pathogenic by multiple other diagnostic laboratories (ClinVar #42874). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | This missense variant replaces arginine with cysteine at codon 663 in the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 15858117, 18533079, 20350521, 23674513, 27532257, 31568572). A different variant occurring at the same codon, p.Arg663His, is a well documented pathogenic mutation (Clinvar variation ID: 42875), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 663 of the MYH7 protein (p.Arg663Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 15563892, 15858117, 18383048, 20800588, 22112859, 23233322, 23283745, 23690394). ClinVar contains an entry for this variant (Variation ID: 42874). 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 disrupts the p.Arg663 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10750581, 11133230). 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. - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 15, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 06, 2022 | This missense variant replaces arginine with cysteine at codon 663 in the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 15858117, 18533079, 20350521, 23674513, 27532257, 31568572). A different variant occurring at the same codon, p.Arg663His, is a well documented pathogenic mutation (Clinvar variation ID: 42875), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Klaassen Lab, Charite University Medicine Berlin | Jul 03, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Sep 17, 2014 | - - |
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 | Jul 01, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The p.R663C pathogenic mutation (also known as c.1987C>T), located in coding exon 16 of the MYH7 gene, results from a C to T substitution at nucleotide position 1987. The arginine at codon 663 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 numerous individuals with hypertrophic cardiomyopathy (HCM) from various ethnic groups (Van Driest SL et al, J. Am. Coll. Cardiol. 2004 Aug; 44(3):602-10; Yu B et al, J. Clin. Pathol. 2005 May; 58(5):479-85; Wang S et al, Clin Cardiol 2008 Mar; 31(3):114-8; Kassem HSh et al, J Cardiovasc Transl Res 2013 Feb; 6(1):65-80; Zhao Y et al. Int. J. Mol. Med., 2016 Jun;37:1511-20; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). Other variants at the same codon, p.R663H (c.1988G>A) and p.R663S (c.1987C>A), have been detected in individuals with HCM (Gruver EJ et al, Am. J. Cardiol. 1999 Jun; 83(12A):13H-18H; Richard P et al, Circulation 2003 May; 107(17):2227-32). This amino acid position is highly conserved in available vertebrate species. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
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 T665 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at