rs727503278

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM2PP1_StrongPS4

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.427C>T (p.Arg143Trp) variant in MYH7 has been identified in >40 individuals with HCM, including 1 individual in which it was observed in the homozygous state (PS4; Mohiddin 2003 PMID:12820698; Erdmann 2003 PMID:12974739; Maron 2012 PMID:21839045; Curila 2012 PMID:22455086; Liu 2013 PMID:23711808; Kapplinger 2014 PMID:24510615; Chiou 2015 PMID:25086479; Weissler-Snir 2017 PMID:28193612; Mademont-Soler 2017 PMID:28771489; Hershkovitz 2019 PMID:30588760; Gao 2020 PMID:32344918; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Centenary Institute Sydney pers. comm.) and segregated with disease in >9 affected relatives from three families (Mademont-Soler 2017 PMID:28771489 GeneDx pers. comm.; OMGL pers. comm.). It was also identified in 2 infants with DCM that had loss of function variants in MYH7 and both variants segregated with DCM in one affected infant sibling (Ambry pers. comm; LMM pers. comm.). This variant has been identified in 0.002% (FAF 95% CI, 2/18394) of East Asian chromosomes and 0.001% (FAF 95% CI, 4/113754) of European chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). 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 (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014751/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 0.193

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 11 ACMG points.

PS4

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

PM2

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.427C>T	p.Arg143Trp	missense_variant	5/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.427C>T	p.Arg143Trp	missense_variant	4/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.427C>T	p.Arg143Trp	missense_variant	5/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251480

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 16, 2017	p.Arg143Trp (c.427C>T) in the MYH7 gene (NM_000257.3) chr14-23901923-G-A rs727503278 Seen in one patient with HCM in our center. Given the case data and an additional pathogenic variant at the same amino acid position, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Because of its frequency in gnomAD, it has been classified as likely pathogenic and not pathogenic. It should also be re-reviewed periodically given its frequency in gnomAD. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient's family), 5 patients referred for HCM genetic testing, 1 patient with DCM (and an MYH7 loss of function variant in trans). The possibility of overlap of patients is minimal since most of the case reports are published from varying institutions, unless otherwise noted below. There is strong case data and modrate segregation data. Erdmann et al (2003) saw this variant in 1 patient with HCM. Patients recruited were either Turkish, Greek, Italian, or German. Liu et al (2013) reports one patient with this variant, but the c.DNA position is listed as c.533C>T. Kapplinger et al (2014) saw this variant in 6 cases of HCM, (either diagnosed with HCM at Mayo or referred for HCM genetic testing). Chiou et al (2014) reports the variant in 1 Taiwanese patient with HCM. Nomenclature for cDNA is c.533C>T as well. Walsh (2016) reports this variant in 2 patients with clinical diagnosis of HCM. Mademont-Soler (2017) reports this variant in 1 index pt with HCM. Authors note that three other affected family members tested positive, but do not provide degree of relation or other clinical details. Ingles et al (2017) considered this variant pathogenic and have seen this variant in an HCM patient at their center. Maron BJ, et al. (2012) reports this variant in a 32yo male with HCM and family history of SCD who also harbored a splice variant in TPM1. Murphy et al. (2016) identified in 1 patient with HCM recruited from Mayo. This might not be a unique case as patients in this study had genetic testing at clinical labs including Transgenomic (which would be redundant with Kapplinger et al) and LMM. LMM: - a patient with DCM who carried an MYH7 loss of function variant in trans (there is an emerging hypothesis that MYH7 variants may contribute to cardiomyopathy risk in a recessive fashion). -a patient with HCM In Homburger et al 2016, the residue is enriched in HCM cases vs. ExAC. Another variant at the same residue R143Q has been reported as pathogenic/likely pathogenic by 7 laboratories in ClinVar. This R143Q variant has not been seen at our center, nor did I perform a complete review based on the data in ClinVar. It is only present in 1 European individual in gnomAD. The R143W variant has been seen in 7 in 123,126 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 8,624 East Asian individuals (MAF = 0.01160%), 4 of 55,850 European (NF) individuals (MAF = 0.003581%), and 1 of 15,391 South Asian individuals (MAF = 0.003249%). I checked the filtering allele frequency for this variant in ExAC and it passes the threshold for HCM. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 14, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2024	Observed in individuals with cardiomyopathy and/or sudden cardiac death and in unaffected relatives from three families, including one family in which the variant was identified in trans with another MYH7 variant (PMID: 30588760); Reported in a 32 year-old male with a family history of sudden cardiac death, who also harbored a splice site variant in the TPM1 gene (PMID: 21839045); Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (PMID: 27532257, 29300372); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17947214, 19864899, 25086479, 26914223, 27532257, 28615295, 28193612, 12974739, 23711808, 8981935, 3203908, 7909436, 17372140, 25666907, 8614836, 7883988, 20733148, 15322983, 12820698, 24093860, 15563892, 15358028, 18383048, 28771489, 22455086, 31447099, 33309763, 32894683, 32344918, 33673806, 34542152, 34598319, 24510615, 35653365, 36243179, 37652022, HironoK2024[Preprint], 37340232, 28408708, 33495596, 33495597, 21839045, 30588760, 29300372, 36975868, 37461109) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 11, 2024	- -

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the MYH7 protein (p.Arg143Trp). This variant is present in population databases (rs727503278, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 23711808, 25086479, 27532257, 28408708, 28615295, 28771489, 30588760). ClinVar contains an entry for this variant (Variation ID: 164401). 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.Arg143 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 15563892, 21252143, 22765922, 24093860). 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. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Feb 01, 2019	This MYH7 Arg143Trp variant has previously been reported in HCM cohorts (Erdmann J et al., 2003; Van Driest SL et al., 2004; Maron BJ et al., 2011; Liu W et al., 2013; Kapplinger JD et al., 2014; Chiou KR et al., 2014; Mademont-Soler I et al., 2017; Walsh R et al., 2017), and has been been proven to segregate in one family (Mademont-Soler I et al., 2017). We have also identified this variant in one isolated HCM case (Ingles J et al., 2017). This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000028. Interestingly, a different rare variant at this position (Arg143Gln) has been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster and PolyPhen-2 predict this variant to be "deleterious". In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant this variant has been reported in more than 10 unrelated probands (PS4), is rare in the general population (PM2), segregates to affected individuals in one family (PP1) and in silico tools predict the variant is deleterious (PP3), therefore we classify this variant as 'likely pathogenic'. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 11, 2018	The c.427C>T (p.Arg143Trp) variant of the MYH7 gene has been identified in numerous (>15) individuals with Hypertrophic Cardiomyopathy (HCM) (PMID:12974739, 25086479, 26914223, 28408708, 28193612, 23711808, 28615295, 24510615, 24093860, 22765922, 22455086, 15563892, 27532257). This variant has also been reported in compound heterozygous status with a truncating variant (p.Arg1530*) in an individual with fatal dilated cardiomyopathy. In the same study, this variant was found in one individual with HCM and in a parent with mild septum hypertrophy of this individual , as well as in another individual with HCM and in the two asymptomatic siblings (67 and 70 yeas old, respectively) of this individual, suggesting incomplete penetrance (PMID: 30588760). In silico computational prediction suggests that the p.Arg143Trp variant may have deleterious effect on the protein function (REVEL score: 0.892). This variant is found to be rare (0.00002784) in the general population database (gnomAD). Another amino acid substitution at the same location (p.Arg143Gln) has been interpreted as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation expert panel (ClinVar ID: 43006). Therefore, the c.427C>T (p.Arg143Trp) variant in the MYH7 gene is classified as likely pathogenic. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 12, 2022	This missense variant replaces arginine with tryptophan at codon 143 of 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 25086479, 26914223, 27532257, 28408708, 28193612, 30588760, 32344918, 33495596, 33495597, 34598319; ClinVar SCV000199274.4), as well as in six individuals affected with or suspected of having hypertrophic cardiomyopathy (PMID: 24510615). Four family members of these probands have been reported to be unaffected carriers (PMID: 30588760). This variant has also been identified in a case of fetal left ventricular noncompaction (PMID: 33309763). This variant has been identified in 7/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg143Gln (Clinvar variation ID 43006), is known to cause familial hypertrophic cardiomyopathy, suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 29, 2021	- -

Hypertrophic cardiomyopathy 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Feb 15, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	May 27, 2019	PS4, PM5, PP3 -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2017

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

The p.R143W variant (also known as c.427C>T), located in coding exon 3 of the MYH7 gene, results from a C to T substitution at nucleotide position 427. The arginine at codon 143 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Erdmann J et al. Clin. Genet. 2003;64:339-49; Chiou KR et al. J Cardiol. 2015;65:250-6; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Walsh R et al. Genet. Med. 2017;19:192-203). Another variant at the same codon, p.R143Q (c.428G>A), has also been detected in individuals with HCM (Song L et al. Clin. Chim. Acta. 2005;351:209-16). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.93

MutPred

0.79

Gain of catalytic residue at Y142 (P = 2e-04);

MVP

0.98

MPC

2.2

ClinPred

0.92

GERP RS

2.6

Varity_R

0.69

gMVP

0.95

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