Submissions for variant NM_000256.3(MYBPC3):c.121C>T (p.Arg41Cys)

gnomAD frequency: 0.00003  dbSNP: rs373638535

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035375	SCV000059023	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	The p.Arg41Cys variant in MYBPC3 has been reported in 2 affected infants with DCM from 1 family, both of whom also carried a likely pathogenic variant in MYH7 (Miller 2013, LMM data). It has been identified in 5/124656 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). 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.
Invitae	RCV001046345	SCV001210243	uncertain significance	Hypertrophic cardiomyopathy	2023-10-14	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 41 of the MYBPC3 protein (p.Arg41Cys). 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 individual(s) with dilated cardiomyopathy (PMID: 23054336, 27532257). ClinVar contains an entry for this variant (Variation ID: 42510). 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. 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	RCV001177052	SCV001341179	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 41 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 dilated cardiomyopathy (PMID: 23054336, 24503780, 27532257), and in a stillborn baby (PMID: 30615648). This variant has been identified in 5/272350 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.
CeGaT Center for Human Genetics Tuebingen	RCV002262600	SCV002544565	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496527	SCV002814982	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-08-02	criteria provided, single submitter	clinical testing