ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2938C>T (p.Arg980Cys) (rs397515994)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035543 SCV000059193 uncertain significance not specified 2012-06-28 criteria provided, single submitter clinical testing The Arg980Cys variant in MYBPC3 has not been previously reported in the literatu re nor previously been identified in >3600 individuals (>2200 Caucasian, >300 Bl ack) tested by our laboratory. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity conclusively. Additional information is needed to fully as sess the clinical significance of the Arg980Cys variant.
Blueprint Genetics RCV000208005 SCV000264037 uncertain significance Paroxysmal atrial fibrillation 2015-10-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000303098 SCV000372300 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000360153 SCV000372301 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000267817 SCV000372302 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000360153 SCV000623578 uncertain significance Hypertrophic cardiomyopathy 2018-03-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 980 of the MYBPC3 protein (p.Arg980Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397515994, ExAC 0.01%). This varian has been described in an individual with slightly abnormal ventricular wall thickness and diameter (PMID: 22958901) and in an individual with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42671). 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, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786365 SCV000925165 uncertain significance not provided 2017-11-10 no assertion criteria provided provider interpretation p.Arg980Cys (c.2938C>T) in exon 28 of the MYBPC3 gene (NM_000256.3; chr11-47355529-G-A) SCICD Classification: variant of uncertain significance based on weak case 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. Case data (not including our patient): 3 ClinVar: Laboratory for Molecular Medicine, Blueprint Genetics and Illumina classify this variant as a VUS Cases in the literature: 1 of 3600 patients in the Offspring cohort of the Framingham Heart study and the Jackson Heart Study (observational studies of cardiovascular disease) had this variant (Bick et al 2012; likely reundant with case submitted to ClinVar by LMM and Alfares et al 2015). This patient had a left ventricular wall thickness of 1.07cm and LVDD of 5.34cm, both within the normal range. 1 of 2912 patients with HCM/DCM tested at LMM (Alfares et al 2015; likely redundant with case submitted to ClinVar by LMM and Bick et al 2012) This variant co-occurred with an LP variant in TTN in one of the patients at our center. 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 arginine at codon 980 is strongly conserved across species. Neighboring amino acids are also strongly conserved. Nearby pathogenic variants at this codon or neighboring codons: The only pathogenic variants at nearby codons +/- 10 amino acids are truncating variants. Population data: Highest MAF in European population: 0.004677%. The variant was reported online in 4 of 98,238 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 4 of 42,759 individuals of European descent (MAF=0.005%). 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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