Submissions for variant NM_000256.3(MYBPC3):c.745T>C (p.Cys249Arg)

gnomAD frequency: 0.00001  dbSNP: rs397516071

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035664	SCV000059315	uncertain significance	not specified	2015-05-16	criteria provided, single submitter	clinical testing	The p.Cys249Arg variant in MYBPC3 has been identified by our laboratory in 1 Afr ican American individual with DCM. It has also been identified in 1/8044 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs397516071). Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact to the protein. In s ummary, the clinical significance of the p.Cys249Arg variant is uncertain.
Ambry Genetics	RCV000241606	SCV000320420	uncertain significance	Cardiovascular phenotype	2020-07-02	criteria provided, single submitter	clinical testing	The c.745T>C (p.C249R) alteration is located in exon 6 (coding exon 6) of the MYBPC3 gene. This alteration results from a T to C substitution at nucleotide position 745, causing the cysteine (C) at amino acid position 249 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205568	SCV001376830	uncertain significance	Hypertrophic cardiomyopathy	2024-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 249 of the MYBPC3 protein (p.Cys249Arg). This variant is present in population databases (rs397516071, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42788). 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.
GeneDx	RCV001762112	SCV001989064	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Reported in association with DCM, although no clinical or segregation data were provided (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42788; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)
All of Us Research Program, National Institutes of Health	RCV001205568	SCV004834728	uncertain significance	Hypertrophic cardiomyopathy	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 249 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 at least 1 individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 2/247004 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.