Submissions for variant NM_000256.3(MYBPC3):c.11C>T (p.Pro4Leu)

gnomAD frequency: 0.00001  dbSNP: rs748689012

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774446	SCV000908148	uncertain significance	Cardiomyopathy	2021-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 4 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 cardiovascular disorders in the literature. This variant has been identified in 7/261936 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.
Invitae	RCV001236056	SCV001408768	uncertain significance	Hypertrophic cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the MYBPC3 protein (p.Pro4Leu). This variant is present in population databases (rs748689012, gnomAD 0.007%). 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: 629736). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The leucine 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV002261201	SCV002541144	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002343627	SCV002641615	uncertain significance	Cardiovascular phenotype	2021-02-12	criteria provided, single submitter	clinical testing	The p.P4L variant (also known as c.11C>T), located in coding exon 1 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 11. The proline at codon 4 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV002487587	SCV002788717	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV002261201	SCV004039891	uncertain significance	not provided	2023-03-30	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