ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.712C>T (p.Arg238Cys)

gnomAD frequency: 0.00002  dbSNP: rs771143409
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001181354 SCV001346487 uncertain significance Cardiomyopathy 2023-11-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 238 of the MYBPC3 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who may be affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27194543). This variant has been identified in 4/247642 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001346816 SCV001541048 uncertain significance Hypertrophic cardiomyopathy 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 238 of the MYBPC3 protein (p.Arg238Cys). This variant is present in population databases (rs771143409, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 27194543). ClinVar contains an entry for this variant (Variation ID: 921746). 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. 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.
Ambry Genetics RCV002375071 SCV002668347 uncertain significance Cardiovascular phenotype 2022-11-18 criteria provided, single submitter clinical testing The p.R238C variant (also known as c.712C>T), located in coding exon 6 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 712. The arginine at codon 238 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in an individual with possible arrhythmogenic right ventricular cardiomyopathy (ARVC); however, clinical details were limited (Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003322860 SCV004028152 uncertain significance not provided 2023-08-16 criteria provided, single submitter clinical testing Identified in a patient with onset of DCM as a teenager who also has a pathogenic splice variant in the MYBPC3 gene (Bagnall et al., 2022); Described in association with ARVC with conflicting evidence (Medeiros-Domingo et al., 2016; Ye et al., 2019; Costa et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31402444, 33232181, 27194543, 36252119)
Mayo Clinic Laboratories, Mayo Clinic RCV003322860 SCV004226162 uncertain significance not provided 2022-11-17 criteria provided, single submitter clinical testing PP3, PM2_supporting

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