ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2381C>T (p.Pro794Leu) (rs730880565)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208362 SCV000264036 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-26 criteria provided, single submitter clinical testing
Color RCV000777945 SCV000914043 uncertain significance Cardiomyopathy 2018-08-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 27/199418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000628975 SCV000749885 uncertain significance Hypertrophic cardiomyopathy 2017-10-16 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 794 of the MYBPC3 protein (p.Pro794Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs730880565, ExAC 0.06%). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 180968). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454991 SCV000539828 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been previously reported in the literature, but has been reported in ClinVar 180968. Variant absent from pop databases, no publications. ClinVar 2 star likely path classifcation by GeneDX with inadequate evidence
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786368 SCV000925172 uncertain significance not provided 2017-11-01 no assertion criteria provided provider interpretation p.Pro794Leu (c.2381C>T) in exon 24 of the MYBPC3 gene (NM_000256.3; chr11-47359273-G-A) SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and lack of segregation data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYBPC3: Pathogenic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). However, there are several missense variants in MYBPC3 known to cause disease. MYBPC3 encodes cardiac myosin-binding protein C. It binds myosin heavy chain and titin. Phosphorylation of MYBPC3 modulates contraction of the sarcomere. Region level data: Amr et al 2016: patients with HCM with variants in this region are overrepresented compared to controls. Case data (not including our patient): at least 3 · ClinVar: § GeneDx (likely path), Laboratory for Molecular Medicine (VUS) and Blueprint Genetics (VUS): § LMM saw this variant in a whole exome/genome case but was not fully reviewed. § GeneDx saw this variant in one patient with HCM who had another pathogenic variant. However, neither of these variants have been reviewed since updated variant classification guidelines were published § Blueprint has downgraded their classification of this variant to VUS from likely path. · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The proline at codon 794 is not completely conserved across species. Nearby pathogenic variants at this codon or neighboring codons: A truncating variant at this codon, p.Pro794fs*26, is reported in 1 of ~400 patients with HCM (Van Driest et al 2004). Other truncating variants are nearby (p.Gln791Ter, p.Trp792Valfs, p.Trp792Ter, p.Pro795Leufs, p.Gly799Trpfs). A missense variant at a nearby codon is classified as pathogenic by multiple labs: p.Trp792Arg. Population data: Highest MAF in the South Asian population: 0.079%. The variant was reported online in 27 of 99,709 individuals 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, Ashkenazi, Latino descent. Specifically, the variant was observed in 19 of 12,073 individuals of South Asian descent (MAF=0.079%), 1 of 2,571 individuals of "other" descent, 6 of 41,715 individuals of European descent and 1 of 13,128 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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