rs121913642

Positions:

• chr14-23427879-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP1_Strong PM1 PM2 PS3 PP3 PS4_Supporting

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
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.11

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 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/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.1594T>C	p.Ser532Pro	missense_variant	16/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1594T>C	p.Ser532Pro	missense_variant	15/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1594T>C	p.Ser532Pro	missense_variant	16/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 24, 2023	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. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2021	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 07, 2000

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 14, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

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). 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: 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

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	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.84	P
Vest4		0.98
MutPred		0.71		Gain of catalytic residue at S532 (P = 2e-04);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.92
gMVP		1.0

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

Other links and lift over

dbSNP: rs121913642; hg19: chr14-23897088;