Submissions for variant NM_000257.4(MYH7):c.1594T>C (p.Ser532Pro)

dbSNP: rs121913642

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000211832	SCV000564417	pathogenic	Primary dilated cardiomyopathy	2016-12-15	reviewed by expert panel	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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211832	SCV000199219	pathogenic	Primary dilated cardiomyopathy	2014-08-21	criteria provided, single submitter	clinical testing	The Ser532Pro variant in MYH7 has been reported in one large family with DCM and segregated with disease in 15 affected relatives (Kamisago 2000). This variant was also absent from large population studies. A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with DCM (Schmitt 2006, Debold 2007, Palmer 2013). Serine (Ser) at position 532 is hi ghly conserved in mammals and across evolutionarily distant species and the chan ge to proline (Pro) was predicted to be pathogenic using a computational tool cl inically validated by our laboratory. This tool's pathogenic prediction is estim ated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://www.partners.org/personaliz edmedicine/LMM) based upon segregation studies, absence from controls, and funct ional evidence.
Invitae	RCV000688025	SCV000815621	pathogenic	Hypertrophic cardiomyopathy	2023-12-21	criteria provided, single submitter	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). 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.
GeneDx	RCV001570405	SCV001794696	pathogenic	not provided	2020-10-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 22949430, 27532257, 29300372, 25937279, 23313350, 17351073, 16983074, 11106718)
Ambry Genetics	RCV002399325	SCV002709732	pathogenic	Cardiovascular phenotype	2019-09-27	criteria provided, single submitter	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, and is located in the head domain. 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468970	SCV002765997	pathogenic	Cardiomyopathy	2022-11-14	criteria provided, single submitter	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.
OMIM	RCV000015164	SCV000035421	pathogenic	Dilated cardiomyopathy 1S	2000-12-07	no assertion criteria provided	literature only