Submissions for variant NM_000256.3(MYBPC3):c.2815C>T (p.Arg939Trp)

gnomAD frequency: 0.00001  dbSNP: rs534366414

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455020	SCV000539825	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 HCM proband
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769312	SCV000900690	uncertain significance	Cardiomyopathy	2018-04-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769312	SCV001351109	uncertain significance	Cardiomyopathy	2023-06-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 939 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 hypertrophic cardiomyopathy (PMID: 21750094), in an individual affected with dilated cardiomyopathy (PMID: 31983221), and in an individual affected with noncompaction cardiomyopathy (PMID: 30847666). This variant has been identified in 9/278532 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000609678	SCV001369920	uncertain significance	Hypertrophic cardiomyopathy 4	2019-04-23	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Invitae	RCV001232158	SCV001404704	uncertain significance	Hypertrophic cardiomyopathy	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 939 of the MYBPC3 protein (p.Arg939Trp). This variant is present in population databases (rs534366414, gnomAD 0.008%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21750094). ClinVar contains an entry for this variant (Variation ID: 403204). 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	RCV002436369	SCV002749478	uncertain significance	Cardiovascular phenotype	2023-08-02	criteria provided, single submitter	clinical testing	The p.R939W variant (also known as c.2815C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2815. The arginine at codon 939 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Waldm&uuml;ller S et al. Eur. J. Heart Fail. 2011;13:1185-92). This variant was also detected in a cardiomyopathy genetic testing cohort case; however, clinical details were limited, and an additional cardiac variant was detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).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 alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000609678	SCV000733035	uncertain significance	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001701005	SCV001923309	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701005	SCV001973977	uncertain significance	not provided		no assertion criteria provided	clinical testing