Submissions for variant NM_000256.3(MYBPC3):c.1960C>T (p.Arg654Cys)

gnomAD frequency: 0.00002  dbSNP: rs397515939

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035455	SCV000059103	uncertain significance	not specified	2014-12-17	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg654Cys var iant 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 adu lt with HCM, who carried another pathogenic MYBPC3 variant sufficient to explain disease. In addition, this variant has been identified in 1/67617 European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs397515939). Arginine (Arg) at position 654 is not conserved in mammal s or evolutionarily distant species and the change to cysteine (Cys) was predict ed to be benign using a computational tool clinically validated by our laborator y. This tool's benign prediction is estimated to be correct 89% of the time (Jor dan 2011). In summary, while the clinical significance of the p.Arg654Cys varian t is uncertain, these data suggest that it is more likely to be benign.
Invitae	RCV000465226	SCV000546485	uncertain significance	Hypertrophic cardiomyopathy	2024-01-03	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 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). 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.
Color Diagnostics, LLC DBA Color Health	RCV001177056	SCV001341183	uncertain significance	Cardiomyopathy	2022-10-11	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002482957	SCV002790647	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177056	SCV003838275	uncertain significance	Cardiomyopathy	2022-03-28	criteria provided, single submitter	clinical testing