14-23427879-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4_SupportingPP1_StrongPM1PM2PS3PP3

This summary comes from the ClinGen Evidence Repository: The c.1594T>C (p.Ser532Pro) variant in MYH7 has been reported in 2 individuals with dilated cardiomyopathy (PS4_Supporting; PMID:11106718; PMID:22949430; Partners LMM ClinVar SCV000199219.4). This variant segregated with disease in >10 affected individuals (PP1_Strong; PMID:11106718; PMID:22949430). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with DCM (PS3; PMID:16983074; PMID:23313350; PMID:17351073 ). 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). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS3; PP1_ Strong; PM1; PM2; PP3; PS4_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA011011/MONDO:0005021/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 9.11

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1S
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
MYH7-related skeletal myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
myopathy, myosin storage, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
myopathy, myosin storage, autosomal dominant
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
congenital myopathy 7A, myosin storage, autosomal dominant
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ebstein anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyaline body myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

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

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.

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 rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.1594T>C	p.Ser532Pro	missense_variant	Exon 16 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.1594T>C	p.Ser532Pro	missense_variant	Exon 15 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.1594T>C	p.Ser532Pro	missense_variant	Exon 16 of 40	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.1594T>C	p.Ser532Pro	missense_variant	Exon 16 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.1594T>C	p.Ser532Pro	missense_variant	Exon 15 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:3

Dec 15, 2016

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1594T>C (p.Ser532Pro) variant in MYH7 has been reported in 2 individuals with dilated cardiomyopathy (PS4_Supporting; PMID:11106718; PMID:22949430; Partners LMM ClinVar SCV000199219.4). This variant segregated with disease in >10 affected individuals (PP1_Strong; PMID:11106718; PMID:22949430). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with DCM (PS3; PMID:16983074; PMID:23313350; PMID:17351073 ). 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). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS3; PP1_ Strong; PM1; PM2; PP3; PS4_Supporting -

Feb 24, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with proline at codon 532 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). Transgenic mouse models indicate that this variant disrupts the function of the MYH7 protein, causing depressed contractile function and reduced myocardial stiffness compared to controls, resulting in a phenotype consistent with dilated cardiomyopathy (PMID: 16983074, 23313350). This variant has been reported in at least 2 individuals affected with dilated cardiomyopathy (PMID: 11106718, 11106718, 29300372). It has been shown that this variant segregates with disease in at least 16 affected family members across several generations in one family (PMID: 11106718). 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 Pathogenic. -

Oct 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser542Pro variant in MYH7 has been reported in two individuals, including one large family with DCM and segregated with disease in 15 affected relatives (Kamisago 2000 PMID: 11106718, Kelly 2018 PMID: 29300372, LMM data). It was absent from large population studies. Animal models in mice have shown that this variant disrupts the function of MYH7 and leads to a phenotype consistent with DCM (Schmitt 2006 PMID: 16983074, Debold 2007 PMID: 17351073, Palmer 2013 PMID: 23313350, Aksel 2015 PMID: 25937279). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 2017 PMID 27532257). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant dilated cardiomyopathy. ACMG/AMP Criteria applied: PS3, PP1_Strong, PM1, PM2_Supporting, PP3, PS4_Supporting. -

Dilated cardiomyopathy 1S

Pathogenic:1

Dec 07, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cardiomyopathy

Pathogenic:1

Nov 14, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYH7 c.1594T>C (p.Ser532Pro) 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 251226 control chromosomes. c.1594T>C has been reported in the literature to segregate in multiple individuals affected with Cardiomyopathy (example: Kamisago_2000). 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 (Debold_2007, Schmitt_2006 and Palmer_2013). These studies show a significant decrease in maximal force generating capacity and slower velocity of actin movment resulting in slower rates of myocyte shortening. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Jul 05, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate impaired contractile function that results in left ventricular dilation (Schmitt et al., 2006; Debold et al., 2007; Palmer et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel; This variant is associated with the following publications: (PMID: 17351073, 23313350, 25937279, 29300372, 22949430, 27532257, 11106718, 16983074) -

Hypertrophic cardiomyopathy

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 532 of the MYH7 protein (p.Ser532Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 11106718). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14108). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 16983074, 17351073, 23313350, 25937279). 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. -

Cardiovascular phenotype

Pathogenic:1

Oct 17, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S532P pathogenic mutation (also known as c.1594T>C), located in coding exon 14 of the MYH7 gene, results from a T to C substitution at nucleotide position 1594. The serine at codon 532 is replaced by proline, an amino acid with similar properties. This variant has been reported in dilated cardiomyopathy (DCM) cases, including one family with co-segregation in numerous affected relatives (Kamisago M et al. N. Engl. J. Med., 2000 Dec;343:1688-96; Lakdawala NK et al. Circ Cardiovasc Genet, 2012 Oct;5:503-10). Heterozygous mouse models demonstrated impaired contractile function with progressive DCM phenotypes (Schmitt JP et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Sep;103:14525-30; Aksel T et al. Cell Rep, 2015 May;11:910-920). 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

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

PhyloP100

9.1

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.84

Vest4

0.98

MutPred

0.71

Gain of catalytic residue at S532 (P = 2e-04);

MVP

1.0

MPC

2.3

ClinPred

1.0

GERP RS

4.9

Varity_R

0.92

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over