Submissions for variant NM_000256.3(MYBPC3):c.756C>A (p.Phe252Leu)

dbSNP: rs876661367

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001213637	SCV001385280	uncertain significance	Hypertrophic cardiomyopathy	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 252 of the MYBPC3 protein (p.Phe252Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 30297972, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 235022). 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.
GeneDx	RCV001589162	SCV001826925	uncertain significance	not provided	2019-11-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30297972)
Ambry Genetics	RCV002390591	SCV002672887	uncertain significance	Cardiovascular phenotype	2020-10-06	criteria provided, single submitter	clinical testing	The p.F252L variant (also known as c.756C>A), located in coding exon 6 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 756. The phenylalanine at codon 252 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Ho CY et al. Circulation, 2018 10;138:1387-1398). This amino acid position is highly 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223889	SCV000280280	uncertain significance	not specified	2011-11-09	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. p.Phe252Leu (c.756C>A) in the MYBPC3 gene. This is a variant that may or may not be associated with disease; there is currently insufficient data available on the variant to determine if it causes cardiomyopathy. The variant is novel (as of November 30th, 2011). This is a chemically conservative change with a non-polar neutral phenylalanine replaced with a non-polar, neutral leucine. The phenylalanine at position 252 is completely conserved across species and isoforms. In silico analysis (Polyphen) predicts the variant to be possibly damaging. The variant was not observed in 400 presumably healthy individuals of various ethnicities at PGxHealth. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~10,000 alleles from Caucasian and African American individuals (as of November 30th, 2011). Further data will be needed on this variant to clarify whether it is disease causing.