Submissions for variant NM_000256.3(MYBPC3):c.2198G>A (p.Arg733His)

gnomAD frequency: 0.00003  dbSNP: rs534345197

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158442	SCV000208377	uncertain significance	not provided	2020-07-22	criteria provided, single submitter	clinical testing	Identified independently and in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data is limited or absent at this time; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20800588, 27532257, 19150014)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000611582	SCV000743556	uncertain significance	Hypertrophic cardiomyopathy 4	2016-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770336	SCV000901770	uncertain significance	Cardiomyopathy	2022-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000611582	SCV001138298	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001047239	SCV001211179	uncertain significance	Hypertrophic cardiomyopathy	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 733 of the MYBPC3 protein (p.Arg733His). This variant is present in population databases (rs534345197, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19150014, 27532257). ClinVar contains an entry for this variant (Variation ID: 181126). 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 tolerated. 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	RCV000770336	SCV001340864	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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: 19150014, 27532257, 27600940, 29764897, 32841044, 33495596). This variant has been identified in 14/280128 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	RCV002426775	SCV002730701	uncertain significance	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	The p.R733H variant (also known as c.2198G>A), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2198. The arginine at codon 733 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with a TNNT2 variant in an individual with hypertrophic cardiomyopathy (HCM), and was also detected in unaffected relatives (Garc&iacute;a-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56). This variant has also been detected in HCM cohorts; however, detail was limited (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Sheikh N et al. Circulation. 2018 09;138(12):1184-1194). A different variant affecting this codon (p.R733C,c.2197C>T) has been detected in HCM cohorts with limited detail (Van Driest SL et al. J. Am. Coll. Cardiol. 2004 Nov;44(9):1903-10.Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species, and histidine 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.
Fulgent Genetics, Fulgent Genetics	RCV002492621	SCV002776091	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-12-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000611582	SCV000733044	uncertain significance	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158442	SCV001970870	uncertain significance	not provided		no assertion criteria provided	clinical testing