rs148808089

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1324C>T(p.Arg442Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,164 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. R442H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.329

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23429037-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 619262.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 14-23429038-G-A is Pathogenic according to our data. Variant chr14-23429038-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23429038-G-A is described in Lovd as [Pathogenic]. Variant chr14-23429038-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.1324C>T	p.Arg442Cys	missense_variant	14/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.1324C>T	p.Arg442Cys	missense_variant	13/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.1324C>T	p.Arg442Cys	missense_variant	14/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251492

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000394

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2019	The p.Arg442Cys variant in MYH7 has been identified in at least 10 individuals with HCM (Laredo 2006, Olivotto 2008, Witjas-Paalberends 2013, Berge 2014, Homburger 2016, Walsh 2017, LMM data). It has also been identified in 6/282878 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177897). Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). Another variant involving this codon, p.Arg442His, has also been identified in individuals with cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM1, PM2, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces arginine with cysteine at codon 442 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 23674513, 24111713, 26332594, 27247418, 27532257, 31308319, 31513939, 31737537, 33407484, 33495597, 34310159). This variant has been identified in 6/282878 chromosomes 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	Invitae	Jan 07, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 442 of the MYH7 protein (p.Arg442Cys). This variant is present in population databases (rs148808089, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710, 18533079, 23674513, 27247418, 27532257, 28615295). ClinVar contains an entry for this variant (Variation ID: 177897). 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. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jan 10, 2019	This MYH7 Arg442Cys variant has been previously reported in 8 unrelated HCM cases (Laredo et al., 2007; Olivotto et al., 2008; Berge & Leren, 2013; Walsh et al., 2017). Olivotto et al. (2008) indicated that this novel variant was tested for cosegregation in affected family members (5 affected relatives of a large Italian family are carriers of the variant; Olivotto I, unpublished data). We have identified this variant in 1 affected HCM individual (Hamilton-Craig et al., 2014; Ingles et al., 2017). The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000014. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. We have identified this variant in 1 affected HCM individual. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2), has been reported in at least 9 probands (PS4_moderate), has shown to segregate in at least 1 HCM family (PP1_moderate) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify this variant as 'likely pathogenic'. -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYH7: PM1, PM2:Supporting, PM5:Supporting, PP1, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	The MYH7 c.1324C>T; p.Arg442Cys variant (rs148808089) is reported in the literature in >15 individuals affected with dilated cardiomyopathy (DCM), or otherwise included in cohorts of cardiomyopathy patients (Chung 2021a, Chung 2021b, Dejgaard 2017, eMERGE Consortium 2019, Hughes 2021, Mattivi 2020, Norrish 2019, Robyns 2020, Stava 2022, Tran Vu 2019, Walsh 2017, Witjas-Paalberends 2013). It is also listed in the ClinVar database as pathogenic (Variation ID: 177897). This variant is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.844). Additionally, other variants at this codon (p.Arg442His) have been reported in individuals with DCM and are considered pathogenic (selected reference: Walsh 2017). Based on available information, the p.Arg442Cys variant is considered to be pathogenic. References: Chung H et al. Contribution of sarcomere gene mutations to left atrial function in patients with hypertrophic cardiomyopathy. Cardiovasc Ultrasound. 2021a Jan 6;19(1):4 PMID: 33407484 Chung H et al. Effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2021b Mar 4;23(1):18. PMID: 33658040 Dejgaard LA et al. Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy. Data Brief. 2017 Sep 12;15:30-39. PMID: 28971120 eMERGE Consortium. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. Am J Hum Genet. 2019 Sep 5;105(3):588-605. PMID: 31447099 Hughes RK et al. Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers. J Am Heart Assoc. 2021 Aug 3;10(15):e020227. PMID: 34310159 Mattivi CL et al. Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing. Circ Genom Precis Med. 2020 Oct;13(5):453-459. PMID: 32894683. Norrish G et al. Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. Circulation. 2019 Jul 16;140(3):184-192. PMID: 31006259 Robyns T et al. Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. Eur J Med Genet. 2020 Mar;63(3):103754. PMID: 31513939. Stava TT et al. Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. Eur J Prev Cardiol. 2022 Oct 18;29(13):1789-1799. PMID: 35653365. Tran Vu MT et al. Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy. Circ J. 2019 Aug 23;83(9):1908-1916. PMID: 31308319. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257 Witjas-Paalberends ER et al. Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. Cardiovasc Res. 2013 Aug 1;99(3):432-41. PMID: 23674513. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 11, 2016	p.Arg442Cys (c.1324C>T) in exon 13 of the MYH7 gene (NM_000257.2) (14:23898247G>A) We have seen this variant in an individual with HCM. Testing was done by Invitae. Given sufficient case data with moderate segregation we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Some functional data is available and the variant is sufficiently rare in available control populations. The variant has been seen in at least 8 unrelated cases of HCM (not including this patient's family). There is strong case data with moderate segregation data and one case of the variant being reported in a case of DCM with another pathogenic variant. The variant was reported by Laredo et al., 2007 in a woman with HCM. No segregation data was reported. Olivotto et al., 2008 in a patient with HCM. The authors noted that the variant segregated with the phenotype. No details were given in the publication, but personal communication reported in the Agnes Ginges ClinVar entry indicates that it was present in 5 affected family members. Witjas-Paalberends et al., 2013 reported the variant in a woman with HCM. Berge et al., 2014 reported 3 HCM probands with the variant. The variant is listed in ClinVar by LMM, classifed as a VUS. They report that they have seen it in one adult with HCM and 1 adult with DCM who carried a pathogenic variant in another gene. It is listed as pathogenic by Anges Ginges Centre for Molecular Cardiology and has been seen by that center in 1 person with HCM. An abstract by Belus et al., 2008 (http://hdl.handle.net/2158/968997) reported that the R442C variant accelerates cardiac myofibril tension generation and relaxation demonstrated previously in established pathogenic MYH7 variant R403Q. Per the Invitae report the arginine residue at codon 442 is highly conserved and there is a large physicochemical difference between arginine and cysteine. The variant was reported online in 1 of 60,705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 8/11/2016). Specifically, the variant was observed in 1 of 33,370 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was also reported in 2 of 2504 people in 1000 Genomes (as of 8/11/2016). Please note that there is an overlap between this population and ExAC. One person was noted to be from Great Britain and the other was noted to be from Vietnam. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 10, 2017	- -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2023	This missense variant replaces arginine with cysteine at codon 442 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 23674513, 24111713, 26332594, 27247418, 27532257, 31308319, 31513939, 31737537, 33407484, 33495597, 34310159). This variant has been identified in 6/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2023

The p.R442C variant (also known as c.1324C>T), located in coding exon 12 of the MYH7 gene, results from a C to T substitution at nucleotide position 1324. The arginine at codon 442 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 individuals with hypertrophic cardiomyopathy (Laredo R et al. Rev Esp Cardiol. 2006;59:1008-18; Witjas-Paalberends ER et al. Cardiovasc. Res. 2013;99:432-41; Berge KE et al. Clin. Genet. 2014;86(4):355-60; Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Chung H et al. Cardiovasc Ultrasound. 2021 Jan;19(1):4). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000177897, PMID:17125710). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PP1_S, PMID: 17125710, 28615295, 18533079, 23674513, 27247418, 27532257) A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000619262, PMID:31513939,17019812). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.844>=0.6, 3CNET: 0.986>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000238). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.33

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MVP

0.98

MPC

2.1

ClinPred

0.95

GERP RS

2.1

Varity_R

0.64

gMVP

0.99

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over