The p.Arg654Cys variant in MYBPC3 has been reported in 1 Caucasian individual with DCM (Waldmuller 2011). The variant has also been identified by our laboratory in 1 Caucasian adult with HCM, who carried another pathogenic MYBPC3 variant sufficient to explain disease. In addition, this variant has been identified in 1/67617 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515939). Arginine (Arg) at position 654 is not conserved in mammals or evolutionarily distant species and the change to cysteine (Cys) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, while the clinical significance of the p.Arg654Cys variant is uncertain, these data suggest that it is more likely to be benign.

The c.1960C>T (p.R654C) alteration is located in exon 21 (coding exon 21) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 1960, causing the arginine (R) at amino acid position 654 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 654 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 30984009) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 5/280564 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.

Variant summary: MYBPC3 c.1960C>T (p.Arg654Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 8e-06 in 249168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1960C>T has been observed in individual(s) affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (examples: Waldmller_2011, Lopes_2015, Kresin_2019, McGurk_2023, Voinescu_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21750094, 25351510, 37652022, 38473809, 30984009). ClinVar contains an entry for this variant (Variation ID: 42587). Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces arginine with cysteine at codon 654 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 30984009) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 5/280564 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 654 of the MYBPC3 protein (p.Arg654Cys). This variant is present in population databases (rs397515939, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 21750094, 25351510, 27532257, 30984009, 37652022). ClinVar contains an entry for this variant (Variation ID: 42587). 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 tolerated. 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.