Submissions for variant NM_000256.3(MYBPC3):c.1456T>G (p.Trp486Gly)

dbSNP: rs397515902

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168775	SCV000059045	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Trp486Gly variant in MYBPC3 has been reported in 2 individuals with HCM (Lakdawala 2011, Walsh 2017). This variant was absent from large population studies. Tryptophan (Trp) at position 486 is highly conserved in mammals and across evolutionarily distant species and the change to glycine (Gly) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additionally, this variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not suggest an impact to splicing, though, this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Trp486Gly variant is uncertain. ACMG/AMP Criteria applied: PM2; PP3; PS4_Supporting.
Invitae	RCV001212900	SCV001384502	uncertain significance	Hypertrophic cardiomyopathy	2020-01-16	criteria provided, single submitter	clinical testing	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. 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. This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 21943931, 27532257). ClinVar contains an entry for this variant (Variation ID: 42531). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with glycine at codon 486 of the MYBPC3 protein (p.Trp486Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine.
GeneDx	RCV001588842	SCV001822220	uncertain significance	not provided	2020-04-24	criteria provided, single submitter	clinical testing	Reported in association with HCM (Lakdawala et al., 2011; Ito et al., 2017; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42531; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; At the mRNA level, c.1456 T>G is located in the second-to-last nucleotide position of exon 16; in silico analysis supports that this variant does not alter splicing and mini-gene assays did not demonstrate this variant alters splicing (Ito et al., 2017); This variant is associated with the following publications: (PMID: 31006259, 21943931, 28679633, 27532257)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149617	SCV003838951	uncertain significance	Cardiomyopathy	2021-10-04	criteria provided, single submitter	clinical testing