Submissions for variant NM_000256.3(MYBPC3):c.2176C>T (p.Arg726Cys)

gnomAD frequency: 0.00011  dbSNP: rs752200396

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000698006	SCV000826644	uncertain significance	Hypertrophic cardiomyopathy	2022-10-09	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 726 of the MYBPC3 protein (p.Arg726Cys). This variant is present in population databases (rs752200396, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19150014). ClinVar contains an entry for this variant (Variation ID: 575705). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	RCV000772981	SCV000906363	uncertain significance	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 726 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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.
GeneDx	RCV001592892	SCV001815063	uncertain significance	not provided	2020-01-31	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 575705; Landrum et al., 2016); 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: 20594303, 19150014, 22765922, 22958901)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000772981	SCV002042153	uncertain significance	Cardiomyopathy	2021-03-12	criteria provided, single submitter	clinical testing
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	RCV002279726	SCV002098093	likely pathogenic	Left ventricular noncompaction 10	2022-02-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002499249	SCV002776582	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323692	SCV004030123	uncertain significance	not specified	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2176C>T (p.Arg726Cys) results in a non-conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) 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 6.1e-05 in 247584 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2176C>T has been reported in the literature in the heterozygous state in an individual affected with hypertrophic cardiomyopathy who was subsequently cited by others (Garcia-Castro_2009, Coto_2012, Gomez_2017), in two cases of sudden unexplained death, one of which was likely attributed to dilated cardiomyopathy (Sanchez_2016) and the other with no conclusive cardiac-related cause (Iglesias_2021), and in two unrelated individuals undergoing genetic testing for congenital abnormalities, one with noncompaction cardiomyopathy and one with multiple congenital abnormalities including Tetralogy of Fallot, both of whom inherited the variant from a presumably unaffected parent (Delea_2022). 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: 22765922, 35885957, 19150014, 28356264, 33919104, 35629155, 27930701). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003372817	SCV004094763	uncertain significance	Cardiovascular phenotype	2023-09-11	criteria provided, single submitter	clinical testing	The p.R726C variant (also known as c.2176C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2176. The arginine at codon 726 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in individuals with varying phenotypes including hypertrophic cardiomyopathy, dilated cardiomyopathy, sudden unexplained death, congenital heart disease, and noncompaction cardiomyopathy (Coto E et al. J Transl Med, 2010 Jul;8:64; Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Iglesias M et al. J Clin Med, 2021 Apr;10; Delea M et al. Genes (Basel), 2022 Jun;13). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000698006	SCV004842383	uncertain significance	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 726 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004546553	SCV005042597	uncertain significance	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing	The missense variant c.2176C>Tp.Arg726Cys in MYBPC3 gene has been reported in individuals affected with hypertrophic cardiomyopathy Sanchez et. al., 2016; Coto et. al., 2012, as well as in an asymptomatic individual García-Castro et. al., 2009. This variant has been reported in one case with sudden cardiac death Ripoll-Vera et. al., 2021. The p.Arg726Cys variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.006% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance. The amino acid change p.Arg726Cys in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 726 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance VUS.
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	RCV001592892	SCV002098089	likely pathogenic	not provided	2022-02-02	flagged submission	clinical testing