ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1418T>C (p.Met473Thr)

dbSNP: rs1226036490
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001347542 SCV001541808 uncertain significance Brugada syndrome 8 2020-10-19 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with HCN4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 473 of the HCN4 protein (p.Met473Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.
GeneDx RCV001773693 SCV001992087 uncertain significance not provided 2019-08-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

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