Submissions for variant NM_000256.3(MYBPC3):c.3676C>T (p.Arg1226Cys)

gnomAD frequency: 0.00004  dbSNP: rs397516033

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197693	SCV000254438	uncertain significance	Hypertrophic cardiomyopathy	2024-10-15	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 1226 of the MYBPC3 protein (p.Arg1226Cys). This variant is present in population databases (rs397516033, gnomAD 0.02%). This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 27532257, 28255936, 31901299, 37652022). ClinVar contains an entry for this variant (Variation ID: 42731). 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.
Ambry Genetics	RCV000244340	SCV000320349	uncertain significance	Cardiovascular phenotype	2022-05-13	criteria provided, single submitter	clinical testing	The c.3676C>T (p.R1226C) alteration is located in exon 33 (coding exon 33) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 3676, causing the arginine (R) at amino acid position 1226 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798088	SCV002042206	uncertain significance	Cardiomyopathy	2019-10-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000786363	SCV002496249	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing	Reported in multiple individuals with hypertrophic cardiomyopathy or sudden death, however, clinical details were limited and at least two patients harbored additional disease-related variants (Kassem et al., 2017; Walsh et al., 2017; Campuzano et al., 2017; Mademont-Soler et al., 2017); 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: 27532257, 28255936, 28771489)
Fulgent Genetics, Fulgent Genetics	RCV002477069	SCV002777390	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035606	SCV004030122	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3676C>T (p.Arg1226Cys) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249220 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.3676C>T has been reported in the literature in individuals affected with Sudden Cardiac Death (Campuzano_2017), Cardiomyopathy (Walsh_2017, Mademont-Soler_2017) and Left Ventricular Noncompaction (Azevedo_2019), without evidence for causality. Co-occurrence with at least one other pathogenic variant has been reported (MYH7 c.2167C>G, p.Arg723Gly, Mademont-Soler_2017), providing supporting evidence for a benign role. 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: 31901299, 28255936, 28771489, 27532257). Six ClinVar submitters have assessed the variant since 2014, all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000197693	SCV004836572	uncertain significance	Hypertrophic cardiomyopathy	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1226 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 5 individual affected with hypertrophic cardiomyopathy (PMID: 28771489, 27532257, doi:10.1016/j.ejmhg.2017.05.002). This variant has been identified in 12/249220 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035606	SCV000059257	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786363	SCV000925160	uncertain significance	not provided	2015-11-12	no assertion criteria provided	provider interpretation