ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs397516033
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197693 SCV000254438 uncertain significance Hypertrophic cardiomyopathy 2023-10-18 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). 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 p.R1226C variant (also known as c.3676C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3676. The arginine at codon 1226 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple hypertrophic cardiomyopathy cohorts with limited clinical details, often with variants in other cardiomyopathy genes (Kassem HS et al. Egyptian J of Med Hum Gen. 2017 18:381-387; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; alsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant 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.
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

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