Submissions for variant NM_000256.3(MYBPC3):c.362C>T (p.Pro121Leu)

dbSNP: rs551888783

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522511	SCV000619318	uncertain significance	not provided	2017-07-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The P121L variant has not been published as pathogenic or benign in association with cardiomyopathy to our knowledge. This variant is observed in 1/1790 (0.06%) alleles from individuals of East Asian ancestry and in 2/8480 alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P121L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and leucine (L) is the wild-type residue at this position in multiple mammalian species. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae	RCV000695171	SCV000823654	uncertain significance	Hypertrophic cardiomyopathy	2022-07-19	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 121 of the MYBPC3 protein (p.Pro121Leu). 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 450709). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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.
Color Diagnostics, LLC DBA Color Health	RCV000772059	SCV000905087	likely benign	Cardiomyopathy	2018-10-04	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845439	SCV000987514	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000772059	SCV001333007	uncertain significance	Cardiomyopathy	2021-08-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002460081	SCV002618104	likely benign	Cardiovascular phenotype	2019-01-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GenomeConnect - Invitae Patient Insights Network	RCV001535661	SCV001749716	not provided	Primary dilated cardiomyopathy; Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.