Submissions for variant NM_000256.3(MYBPC3):c.1372C>T (p.Arg458Cys)

gnomAD frequency: 0.00005  dbSNP: rs377577698

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158078	SCV000208013	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000812569	SCV000952887	uncertain significance	Hypertrophic cardiomyopathy	2023-12-29	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 458 of the MYBPC3 protein (p.Arg458Cys). This variant is present in population databases (rs377577698, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 180931). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001804873	SCV002052584	uncertain significance	Cardiomyopathy	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 458 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 10/276390 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	RCV002381513	SCV002697218	uncertain significance	Cardiovascular phenotype	2021-09-07	criteria provided, single submitter	clinical testing	The p.R458C variant (also known as c.1372C>T), located in coding exon 16 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1372. The arginine at codon 458 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	RCV000158078	SCV001743148	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158078	SCV001918963	uncertain significance	not provided		no assertion criteria provided	clinical testing