The p.Arg272Cys variant in MYBPC3 has been reported in 5 individuals with hypertrophic cardiomyopathy (HCM) and in at least 3 individuals with dilated cardiomyopathy (DCM) as well as 1 possibly affected family member with DCM (Zeller 2006 PMID:16715312, Ehlermann 2008 PMID:18957093, Hershberger PMID:20215591, Millat 2010 PMID:20624503, Morales 2010 PMID: 20458009, Terilinck PMID:23140321, Walsh 2017 PMID: 27532257, Mademonet-Soler PMID:28771489, LMM data). One of the individuals with HCM (age 24) also carried a pathogenic variant in another HCM causing gene (Mademonet-Soler PMID: 28771489). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42794) and has been identified in 0.008% (7/89912) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org. Preliminary results from an vitro functional study provide some evidence that this variant decreases phosphorylation compared to the wild type (Ehlermann 2008 PMID:18957093); however, the clinical significance of this is uncertain. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.

The p.(R272C) variant has been reported previously in association with DCM, HCM, and in one case of peri-partum cardiomyopathy (PMID: 16715312, 18957093, 20215591, 20458009, 20624503, 23140321); however, informative segregation and functional data were not provided.; 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: 27896284, 20458009, 28771489, 23140321, 27532257, 22337857, 20215591, 20624503, 18957093, 29687901, 20800588, 16715312)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 16715312, 27532257). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the MYBPC3 protein (p.Arg272Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dilated cardiomyopathy (DCM), peripartum cardiomyopathy, or hypertrophic cardiomyopathy (HCM) (PMID: 16715312, 20458009, 20624503, 20800588, 23140321, 27532257, 28771489, 37652022). ClinVar contains an entry for this variant (Variation ID: 42794). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 18957093). 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.

The c.814C>T (p.R272C) alteration is located in exon 7 (coding exon 7) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 814, causing the arginine (R) at amino acid position 272 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This missense variant replaces arginine with cysteine at codon 272 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has suggested that this variant may affect phosphorylation of the MyBP-C motif (PMID: 18957093). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 16715312), in an individual affected with peripartum cardiomyopathy (PMID: 20458009), and in four individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 28771489). One of these individuals also carried a pathogenic p.Arg302Gln variant in the PRKAG2 gene, suggesting that this MYBPC3 variant may not have been the primary cause of disease in that individual (PMID: 28771489). This variant has been identified in 9/208346 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.

This missense variant replaces arginine with cysteine at codon 272 of the MYBPC3 protein. Computational prediction tool indicates this variant may have an uncertain impact on protein structure and function. An experimental study has suggested that this variant may affect phosphorylation of the MyBP-C motif (PMID: 18957093). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 16715312), in an individual affected with peripartum cardiomyopathy (PMID: 20458009), and in four individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 28771489). One of these individuals also carried a pathogenic p.Arg302Gln variant in the PRKAG2 gene, suggesting that this MYBPC3 variant may not have been the primary cause of disease in that individual (PMID: 28771489). This variant has been identified in 9/208346 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.