Submissions for variant NM_000256.3(MYBPC3):c.2197C>T (p.Arg733Cys)

gnomAD frequency: 0.00006  dbSNP: rs397515956

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035475	SCV000059123	uncertain significance	not specified	2017-08-29	criteria provided, single submitter	clinical testing	The p.Arg733Cys variant in MYBPC3 has been reported in at least 2 individuals wi th HCM (Van Driest 2004, LMM data). This variant has been identified in 9/126440 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org/; dbSNP rs397515956). This variant has been reported in Cl inVar (Variant ID: 42607). Arginine (Arg) at position 733 is not conserved in m ammals, or evolutionarily distant species and the change to cystine (Cys) was pr edicted to be benign using a computational tool clinically validated by our labo ratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, this amino acid change is present in the rhesus mac aque. In summary, the clinical significance of the p.Arg733Cys variant is uncer tain.
GeneDx	RCV000766347	SCV000208078	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Reported in individuals referred for HCM genetic testing at GeneDx and in the published literature (PMID: 15519027, 27532257) as well as in one control individual (PMID: 24510615); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 24510615, 34426522, 21310275, 30681346, 30937429, 26659599, 31983221, 15519027)
Invitae	RCV000227952	SCV000284223	uncertain significance	Hypertrophic cardiomyopathy	2022-09-19	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 733 of the MYBPC3 protein (p.Arg733Cys). This variant is present in population databases (rs397515956, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 27532257). ClinVar contains an entry for this variant (Variation ID: 42607). An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515397	SCV000611409	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-01	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677325	SCV000803547	uncertain significance	Hypertrophic cardiomyopathy 4	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Cardiomyopathy, familial hypertrophic, 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting =>PM2 downgraded in strength to Supporting.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000227952	SCV000996343	uncertain significance	Hypertrophic cardiomyopathy	2017-03-22	criteria provided, single submitter	research	This MYBPC3 Arg733Cys variant has been reported in 1 HCM proband by Van Driest et al. (2004) in their cohort of 389 unrelated HCM probands, where only the MYBPC3 gene was screened and 2 HCM probands by Walsh et al. (2017). The variant has also been identified in 1 control (Kapplinger JD, et al., 2014) and is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00008, which is higher then expected for HCM. We have identified this variant in 1 HCM proband who experienced a resuscitated cardiac arrest. This proband also carries an additional known pathogenic splice variant in MYBPC3 (c.1928-2A>G). Computational analyses (SIFT, MutationTaster) support a potentially deleterious effect. However, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this variant to have a "benign" affect. Based on the elevated allele frequency in the general population, observation of the variant in 1 control and a total of 4 HCM probands, we classify MYBPC3 Arg733Cys as variant of "uncertain significance".
Mendelics	RCV000677325	SCV001138299	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188106	SCV001355078	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 733 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 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 27532257, 33782553). This variant has been identified in 17/280042 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	RCV002426551	SCV002729476	uncertain significance	Cardiovascular phenotype	2021-06-08	criteria provided, single submitter	clinical testing	The p.R733C variant (also known as c.2197C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2197. The arginine at codon 733 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM), although clinical details were limited (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035475	SCV000280232	uncertain significance	not specified	2015-02-25	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg733Cys Given weak case data and the fact that few pathogenic variants in MYBPC3 are missense, we consider it a variant of uncertain significance. The variant has been seen in at least one case of HCM (not including this patient's family). There is no segregation data available. Dr. Ackerman's group reported the variant in one patient with HCM from their 389 patient Mayo cohort (van Driest et al 2004). No ancestry or segregation data was reported. They only analyzed MYBPC3 in that study. The arginine at codon 733 is only partially conserved across species, with a histidine at that position in some non-mammals. This is a non-conservative amino acid substitution (Grantham score 180). I could find only one nearby missense variant (p.Arg726Cys (HGMD, Seidmans' database)). Of note, the majority of disease-causing variants in MYBPC3 are splice, nonsense, or frameshift variants. The splicing algorithms that mutationtaster uses did not predict a significant effect on splicing.