Submissions for variant NM_000256.3(MYBPC3):c.799C>G (p.Leu267Val)

gnomAD frequency: 0.00004  dbSNP: rs370941975

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434041	SCV000519078	likely benign	not specified	2015-09-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000539055	SCV000623622	uncertain significance	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the MYBPC3 protein (p.Leu267Val). This variant is present in population databases (rs370941975, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 380700). 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.
Ambry Genetics	RCV000620272	SCV000740002	uncertain significance	Cardiovascular phenotype	2019-07-17	criteria provided, single submitter	clinical testing	The p.L267V variant (also known as c.799C>G), located in coding exon 7 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 799. The leucine at codon 267 is replaced by valine, an amino acid with highly similar properties. This variant was reported in a cardiomyopathy genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507792	SCV001713571	uncertain significance	not provided	2021-02-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532099	SCV004358767	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 267 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: 27532257). This variant has been identified in 4/213764 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.