Submissions for variant NM_000256.3(MYBPC3):c.1255C>T (p.Arg419Cys)

gnomAD frequency: 0.00006  dbSNP: rs368770848

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035381	SCV000059029	uncertain significance	not specified	2012-11-07	criteria provided, single submitter	clinical testing	The Arg419Cys variant in MYBPC3 has not been reported in the literature nor prev iously identified by our laboratory. This variant has been identified in 1/8466 European American chromosomes from a broad population screened by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) suggest that the Arg419Cys variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Arg419Cy s variant. Of note, our laboratory has not detected any variants that meet curr ent criteria to be classified as likely pathogenic or pathogenic in >700 individ uals with DCM.
GeneDx	RCV000766328	SCV000208008	uncertain significance	not provided	2024-07-18	criteria provided, single submitter	clinical testing	Identified in patients with HCM, DCM, and sudden death in published literature (PMID: 36264615, 35629155, 32101375, 30847666); 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: 32101375, 36264615, 35629155, 30847666)
Blueprint Genetics	RCV000208312	SCV000264024	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529358	SCV000623520	uncertain significance	Hypertrophic cardiomyopathy	2025-01-30	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 419 of the MYBPC3 protein (p.Arg419Cys). This variant is present in population databases (rs368770848, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy/hypertrophic cardiomyopathy (PMID: 30847666, 36264615). ClinVar contains an entry for this variant (Variation ID: 42516). 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	RCV000777943	SCV000914041	uncertain significance	Cardiomyopathy	2023-05-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 419 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666) and in an individual affected with sudden unexplained death (PMID: 32101375). This variant has been identified in 8/275120 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035381	SCV004223165	uncertain significance	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1255C>T (p.Arg419Cys) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 243732 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1255C>T has been reported in the literature in individuals affected with Cardiomyopathy (Van Lint_2019, Bourfiss_2022), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with 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: 36264615, 35629155, 30847666). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777943	SCV004239337	uncertain significance	Cardiomyopathy	2023-01-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000529358	SCV004834652	uncertain significance	Hypertrophic cardiomyopathy	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 419 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666) and in an individual affected with sudden unexplained death (PMID: 32101375). This variant has been identified in 8/275120 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.
Ambry Genetics	RCV004018740	SCV004938405	uncertain significance	Cardiovascular phenotype	2021-11-08	criteria provided, single submitter	clinical testing	The c.1255C>T (p.R419C) alteration is located in exon 15 (coding exon 15) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 1255, causing the arginine (R) at amino acid position 419 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.