ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1594T>C (p.Ser532Pro) (rs121913642)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited 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; 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,Partners HealthCare 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 ( edmedicine/LMM) based upon segregation studies, absence from controls, and funct ional evidence.
Invitae RCV000688025 SCV000815621 likely pathogenic Hypertrophic cardiomyopathy 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 532 of the MYH7 protein (p.Ser532Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in a large multigenerational family (PMID: 11106718). ClinVar contains an entry for this variant (Variation ID: 14108). A mouse model expressing this variant has been shown to develop dilated cardiomyopathy. Both homozygous and heterozygous mice developed the disease (PMID: 16983074). Most experimental studies using homozygous mice indicate that this missense change reduces the force-generating capacity and the velocity of actin filament sliding (PMID: 16983074, 17351073, 25937279). However, this notion has been challenged in a study using ventricular strips from heterozygous mice that showed elevated rates of force development (PMID: 23313350). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000015164 SCV000035421 pathogenic Dilated cardiomyopathy 1S 2000-12-07 no assertion criteria provided literature only

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