chr14-23429278-C-T

Position:

• chr14-23429278-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS4 PP3 PS3 PM1 PM5 PM2 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1208G>A (p.Arg403Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy and segregated with disease in >30 affected family members (PS4 and PP1_Strong; PMID:1638703; PMID:1975517; PMID:7789380; PMID:12975413; PMID:24268868; PMID:10725281; PMID:20800588; PMID:12707239; PMID:27532257; AGCMC Sydney ClinVar SCV000692503.1; Invitae ClinVar SCV000253815.4; Partners LMM ClinVar SCV000059359.5; SHaRe consortium, PMID:30297972). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:8614836). This variant was absent from large population studies (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.1207C>T (p.Arg403Trp) - Variation ID 14102). 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; PP1_ Strong; PM1; PM2; PM5; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA010365/MONDO:0005045/002

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 7.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1208G>A	p.Arg403Gln	missense_variant	13/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1208G>A	p.Arg403Gln	missense_variant	12/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1208G>A	p.Arg403Gln	missense_variant	13/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 01, 2013	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. Based on the data reviewed below we consider this variant very likely disease causing. The variant has been seen in at least 12 unrelated cases of HCM with strong segregation data in multiple large kindreds. This variant was the first variant ever associated with HCM. Gesiterfer-Lowrance et al (1990) reported a large French-Canadian family in which 40 family members were affected and shown to have this variant. The same authors later reported the variant in an additional proband (Watkins et al 1992). Epstein et al (1992) reported a kindred with 10 affected individuals with p.Arg403Gln. Marian et al (1994) reported two additional large kindreds with strong segregation data. Goncalves et al (2000) also reported at least one family with HCM and this variant (article unavailable). Richard et al (2003) reported the variant in one individual with HCM. Mohiddin et al (2003) reported the variant in a patient with HCM. Woo et al (2003) reported a kindred with 7 affected individuals with the variant. Van Driest et al (2004) reported one individual with HCM and this variant. We have seen this variant in two unrelated cases of HCM in our center. A mouse model with p.Arg403Gln recapitulates the HCM phenotype (Gesiterfer-Lowrance et al 1996). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Trp (very likely disease causing), p.Arg403Leu (likely disease causing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Lankford et al (1995) reported that p.Arg403Gln lowered the force/stiffness ratio and depressed the velocity of shortening of slow twitch muscle fibers. Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5100 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 100 (RIchard et al 2003. Early papers on this variant did not report control data. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MYH7: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Expression of p.(R403Q) in a transgenic mouse model and subsequent functional studies of mutant myosin heavy chain confirmed the pathogenicity of this variant and suggested that this variant may perturb normal kinetic and mechanic assembly and function of cardiac myosin with a gain-of-function effect (Tyska et al., 2000; Yamashita et al., 2000; Debold et al., 2007); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23751935, 9826622, 10606622, 15001446, 10066683, 17987111, 18480046, 17351073, 28166811, 20031618, 7873324, 29300372, 31783775, 31513939, 34542152, 24928957, 22735528, 18565996, 20811150, 9884344, 22213221, 11227787, 9172070, 8614836, 26601291, 24268868, 27247418, 21310275, 27532257, 15358028, 1638703, 10764406, 29212898, 30508693, 31006259, 32284968, 30847666, 8281650, 33906374, 9183600, 33012304, 33673806, 32746448, 32894683, 35626289, 28193612, 35288587, 10882745, 1975517) -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2017	The p.Arg403Gln variant (rs121913624) is the first, and one of the most well-studied, pathogenic variants to be associated with familial hypertrophic cardiomyopathy (FHC). Segregation analysis of a large French-Canadian kinship first described in Pare et al (1961) revealed the presence of the p.Arg403Gln variant in all affected family members available for testing (Geisterfer-Lowrance 1990). Following discovery in the index family, the p.Arg403Gln variant was subsequently shown to co-segregate with FHC in three additional families (Epstein 1992 and Marian 1994). A mouse model of hypertrophic cardiomyopathy published in 1996 (Geisterfer-Lowrance et al) was generated by introducing the p.Arg403Gln variant into the murine alpha MHC locus. Mice homozygous for this variant died 7 days after birth, whereas heterozygous mice displayed cardiac dysfunction similar to human carriers (Geisterfer-Lowrance 1996). This variant was recently shown to be present at a frequency of 0.12 percent in a combined cohort of dilated and hypertrophic cardiomyopathy patients (identified in 15 out of 12,224 chromosomes; Walsh 2017) while being absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. Additionally, an expert panel has concluded that this variant meets requirements for classification as pathogenic (see link to ClinVar below). -

Hypertrophic cardiomyopathy Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.1208G>A (p.Arg403Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy and segregated with disease in >30 affected family members (PS4 and PP1_Strong; PMID:1638703; PMID:1975517; PMID:7789380; PMID:12975413; PMID:24268868; PMID:10725281; PMID:20800588; PMID:12707239; PMID:27532257; AGCMC Sydney ClinVar SCV000692503.1; Invitae ClinVar SCV000253815.4; Partners LMM ClinVar SCV000059359.5; SHaRe consortium, PMID: 30297972). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:8614836). This variant was absent from large population studies (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.1207C>T (p.Arg403Trp) - Variation ID 14102). 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; PP1_ Strong; PM1; PM2; PM5; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 403 of the MYH7 protein (p.Arg403Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1638703, 1975517, 12975413, 23751935). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14087). 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: 8614836, 9172070, 9826622, 10606622, 10882745, 11227787, 17987111, 18565996). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 22, 2014	The p.Arg403Gln variant in MYH7 is a well-established, common HCM variant that h as been detected in a large number of individuals with HCM and is absent from la rge population studies. Published evidence sufficient to establish a pathogenic role includes presence in multiple families and segregation with disease in more than 10 affected relatives (Geisterfer-Lowrance 1990, Epstein 1992, Marian 1995 , Richard 2003, Millat 2010). Additional studies have been published but are not included here. Our laboratory has identified this variant in 14 families with H CM. The pathogenicity of this variant is further supported by functional studies using animal models (Georgakopoulos 1999, Tyska 2000, Yamashita 2000, Lowey 201 3) and in vitro analyses, which demonstrate an impact on cardiomyocyte function (Di Domenico 2012, Abraham 2013, Witjas-Paalberends 2014). In summary, this vari ant meets our criteria to be classified as pathogenic for HCM in an autosomal do minant manner (http://www.partners.org/personalizedmedicine/LMM). -

Hypertrophic cardiomyopathy 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 13, 2017	The MYH7 Arg403Gln variant has been reported in numerous HCM cases (see literature). This variant is known to have high penetrance and has been described to segregate with disease in multiple large families (Geisterfer-Lowrance AA, et al., 1990; Epstein ND, et al., 1992; Marian AJ, et al.,1995; Richard P, et al., 2003; Woo A, et al., 2003; Millat G, et al., 2010). Many functional studies have been carried out which strongly support the pathogenicity of the variant and its affect on the function of cardiomyocytes (see literature). The variant is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). We identified this variant in an HCM proband, and 1 other affected family member. In silico tools SIFT, PolyPhen-2 and MutationTaster are all supportive of a deleterious role. Furthermore another pathogenic variant has been reported at the same amino acid position (Arg403Trp), suggesting that an amino acid substitution at this residue is not tolerant to change. In summary, based on multiple reported cases, strong segregation data in literature, functional data supportive of pathogenicity and an additional pathogenic variant at the same residue, we classify MYH7 Arg403Gln as a "pathogenic" variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 09, 2022

- -

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

Oct 15, 2021

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 16, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The p.R403Q pathogenic mutation (also known as c.1208G>A), located in coding exon 11 of the MYH7 gene, results from a G to A substitution at nucleotide position 1208. The arginine at codon 403 is replaced by glutamine, an amino acid with highly similar 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) and is has been associated with severe, early onset phenotype (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Kaski JP et al. Circ Cardiovasc Genet, 2009 Oct;2:436-41; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Segregation of this alteration with disease has been observed across multiple families (Geisterfer-Lowrance AA et al. Cell, 1990 Sep;62:999-1006; Epstein ND et al. Circulation, 1992 Aug;86:345-52; Woo A et al. Heart, 2003 Oct;89:1179-85). Many functional studies have demonstrated that this alteration results in enhanced force production in the sarcomere (Tyska MJ et al. Circ. Res., 2000 Apr;86:737-44; Yamashita H et al. J. Biol. Chem., 2000 Sep;275:28045-52; Chuan P et al. Biophys. J., 2012 Jun;102:2782-90; Lowey S et al. J. Biol. Chem., 2013 May;288:14780-7; Witjas-Paalberends ER et al. J. Physiol. (Lond.), 2014 Aug;592:3257-72). 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2023

The MYH7 c.1208G>A variant is predicted to result in the amino acid substitution p.Arg403Gln. This variant was reported has been repeatedly documented to be pathogenic in many individuals with hypertrophic cardiomyopathy (see for example - Geisterfer-Lowrance et al. 1990. PubMed ID: 1975517; Table S1A/B, Walsh et al. 2017. PubMed ID: 27532257). Functional studies confirm this variant impacts MYH7 function (see for example - Debold et al. 2007. PubMed ID: 17351073). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic by multiple labs including the ClinGen cardiomyopathy variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.81		Gain of catalytic residue at L399 (P = 0.0024);
MVP		0.96
MPC		2.3
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913624; hg19: chr14-23898487;