Submissions for variant NM_000256.3(MYBPC3):c.1445C>T (p.Ala482Val) (rs370285346)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000151137	SCV000198920	uncertain significance	not specified	2014-07-24	criteria provided, single submitter	clinical testing	The Ala482Val variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/8366 European American chromos omes and 2/4082 African American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/). Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Ala482Val variant is uncertain.
GeneDx	RCV000766331	SCV000208364	uncertain significance	not provided	2018-02-12	criteria provided, single submitter	clinical testing	This variant is denoted p.Ala482Val (GCG>GTG): c.1445 C>T in exon 16 of the MYBPC3 gene (NM_000256.3). The A482V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports A482V was observed at a low frequency in individuals of African American ancestry (2/4082 alleles) and European ancestry (1/8366 alleles). The A482V substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense mutations in nearby residues (G490V, G490R, W486G, V471E) have been reported in association with HCM, supporting the functional importance of this region of the protein. However, the A482V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000475321	SCV000546481	uncertain significance	Hypertrophic cardiomyopathy	2018-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 482 of the MYBPC3 protein (p.Ala482Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs370285346, ExAC 0.02%). This variant has been observed in individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 25351510, Invitae). However, in some of these individuals, pathogenic alleles were also identified in MYBPC3 and TTN respectively, which suggests that this c.1445C>T variant was not the primary cause of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Phosphorus, Inc.	RCV000578047	SCV000679773	uncertain significance	Left ventricular noncompaction 10	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578099	SCV000679774	uncertain significance	Familial hypertrophic cardiomyopathy 4	2017-08-01	criteria provided, single submitter	clinical testing