rs3218714

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_StrongPM1PM5PM2PP3PS4

This summary comes from the ClinGen Evidence Repository: The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID:30297972). 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.1208G>A p.Arg403Gln - Variation ID 14087). 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; PM5; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA010360/MONDO:0005045/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

14

2

4

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 0.731

Variant links:

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]

MYH7 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

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 linkuse as main transcript	c.1207C>T	p.Arg403Trp	missense_variant	13/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.1207C>T	p.Arg403Trp	missense_variant	12/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1207C>T	p.Arg403Trp	missense_variant	13/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

0.00000342

AC:

5

AN:

1461892

Hom.:

0

Cov.:

34

AF XY:

0.00000275

AC XY:

2

AN XY:

727248

show subpopulations

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

Asia WGS

AF:

0.000577

AC:

2

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 08, 2014	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.Arg403Trp (c.1207C>T) in MYH7 Based on the data reviewed below we consider this variant very likely disease-associated. The variant has been seen in at least 11 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a kindred in which linkage studies pointed towards MYH7. Sequencing of exon 13 of MYH7 identified p.Arg403Trp and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported two families that appear to be distinct from the initial report (Al-Mahdawi et al 1994). Three individuals in one family and two in the other had HCM and carried p.Arg403Trp. Moolman et al (1993) reported the variant segregating with disease in three affected family members. The same authors then report an additional large kindred with 13 affected individuals with the variant (Posen et al 1995). Richard et al (2003) reported the variant in one individual with HCM. The Seidman group reported on proband with the variant online (http://genepath.med.harvard.edu/~seidman/cg3/muts/MYH7_Arg403Trp.html). Perrot et al (2005) reported two affected family members with this variant. Keller et al (2004) reported a patient with severe HCM requiring transplant at 39 years of age who was homozygous for p.Arg403Trp and heterozygous for p.Val896Met in MYBPC3. Erdmann et al (2003) reported two affected family members with the variant. Haluza et al (2001) reported the variant in a 23yo male with HCM who was a compound heterozygote for this variant and p.Arg453His. Interestingly, p.Arg453His was de novo. He inherited p.Arg403Trp from his affected father. 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.Arg403Gln (very likely disease causing), p.Arg403Leu (likely disease causing)) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). 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 5300 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.Arg403Trp is listed in dbSNP, however this seems to refer to its role as an HCM-associated variant (rs3218714). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003), 54 (Moolman et al 1993), 96 (Perrot et al 2005). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	Reported in the apparently homozygous and compound heterozygous state in individuals diagnosed with HCM during adolescence who either developed heart failure and underwent a transplant or experienced ventricular fibrillation arrest and LVNC (Keller et al., 2004; Kolokotronis et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro studies using recombinant and patient-derived myosin harboring R403W suggest that this variant causes an increase in actin-sliding velocity, affinity of myosin for actin, and actin-activated ATPase activity (Yamashita et al., 2000; Keller et al., 2004); Classified in ClinVar as pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID# 14102; ClinVar); This variant is associated with the following publications: (PMID: 10521296, 27532257, 8254035, 21310275, 30217213, 7662452, 7848420, 21239446, 24111713, 15856146, 15010274, 27247418, 18029407, 28615295, 28606303, 28408708, 29540472, 26383716, 29300372, 27476098, 30924982, 31447099, 32344918, 33906374, 33673806, 32659924, 32880476, 10882745, 32894683) -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

Hypertrophic cardiomyopathy 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 22, 2014	This MYH7 Arg403Trp variant is well described in multiple unrelated HCM families (see references). There is strong evidence that the variant co-segregates with disease in several families. Specifically, Posen et al. (1995) presented a large HCM family where the MYH7 Arg403Trp variant was present in 14 clinically affected members. The clinical phenotype observed is variable and disease characteristics range from no hypertrophy to mild left ventricular hypertrophy and/or ECG abnormalities. In addition to being absent in study control cohorts, this variant is also absent in general population databases including 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Furthermore, arginine (Arg) at position 403 is highly conserved across distantly related species, and is a known mutational hotspot region (Dausse E, et al., 1993). We have identified this mutation in one HCM case (no familial segregation possible) in our cohort. Based on the supporting literature and strong evidence of segregation with disease, absence in control cohorts, we classify this MYH7 Arg403Trp variant as "pathogenic". -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 09, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 05, 2018	This c.1207C>T (p. Arg403Trp) variant in the MYH7 gene has been reported in several unrelated patients with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in the reported families (PMID8254035,7662452,.15010274, 17207239, and 18029407). In addition, two different missense variant substitutions affecting the same amino acid position, pArg403Gln and p.Arg403Leu, have been reported in additional patients with HCM (PMID12975413, 1638703, 1975517, 23751935,8254035, 17207239). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p. Arg403Trp change to be deleterious. This c.1207C>T (p. Arg403Trp ) variant in the MYH7 gene is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014102). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014101). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.822>=0.6, 3CNET: 0.992>=0.75). A missense variant is a common mechanism associated with Cardiomyopathy, hypertrophic, 1 . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 04, 2021	This variant was identified as compound heterozygous with NM_000257.4:c.2686G>A._x000D_ Criteria applied: PS4, PM5_STR, PP1_STR, PM1, PM2_SUP, PP2, PP3 -

Cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2019	Variant summary: MYH7 c.1207C>T (p.Arg403Trp) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes (gnomAD). c.1207C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Dausse_1993, Yamashita_2000, Revera_2008, Burns_2017, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The variant has been shown to result in increased actin-sliding velocity and actin-related ATPase activity compared to controls, which may result in reduced myocardial efficiency in patients with the variant (Yamashita_2000, Keller_2004). Patients with the variant were also shown to have reduced systolic and diastolic function as assessed by clinical parameters when compared to non-carrier relatives (Revera_2008). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jan 13, 2020	This variant has been previously reported in multiple individuals with hypertrophic cardiomyopathy and was found to segregate with disease (PMID: 7662452, 17612745, 20428263, 21239446). This variant has been reported in the ClinVar database (Variation ID: 14102). Additionally, a different Pathogenic missense variant in this codon (p.Arg403Gln) has been previously reported in the ClinVar database, which may indicate that this amino acid residue is critical to the function of the protein (Variation ID: 14087). The p.Arg403Trp variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1207C>T (p.Arg403Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1207C>T (p.Arg403Trp) variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 403 of the MYH7 protein (p.Arg403Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypertrophic cardiomyopathy (PMID: 8254035, 18029407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14102). 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: 10882745, 15010274). This variant disrupts the p.Arg403 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1638703, 1975517, 12975413, 23751935). 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, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID: 30297972). 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.1208G>A p.Arg403Gln - Variation ID 14087). 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; PM5; PP3 -

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

Dec 28, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The p.R403W pathogenic mutation (also known as c.1207C>T), located in coding exon 11 of the MYH7 gene, results from a C to T substitution at nucleotide position 1207. The arginine at codon 403 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in individuals and families with hypertrophic cardiomyopathy (HCM), with co-segregation in multiple families demonstrating variable penetrance and expressivity (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; Posen BM et al. Br Heart J, 1995 Jul;74:40-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Functional studies have exhibited increased actin sliding velocity and enzymatic activity (Yamashita H et al. J. Biol. Chem., 2000 Sep;275:28045-52; Keller DI et al. J. Mol. Cell. Cardiol., 2004 Mar;36:355-62). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

D

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D

Eigen

Benign

0.19

Eigen_PC

Benign

-0.070

FATHMM_MKL

Benign

0.61

D

LIST_S2

Uncertain

0.95

D

M_CAP

Pathogenic

0.91

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

0.98

D

MutationAssessor

Pathogenic

3.9

H

MutationTaster

Benign

1.0

A

PrimateAI

Pathogenic

0.91

D

PROVEAN

Pathogenic

-7.0

D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.88

MutPred

0.78

Gain of catalytic residue at R403 (P = 0);

MVP

0.97

MPC

2.2

ClinPred

0.99

D

GERP RS

-0.79

Varity_R

0.86

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3218714; hg19: chr14-23898488; COSMIC: COSV62516821;