ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2875C>G (p.Leu959Val) (rs1057524285)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000444935 SCV000535080 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The L959V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016). The L959V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000560748 SCV000648454 uncertain significance Brugada syndrome 8 2019-07-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 959 of the HCN4 protein (p.Leu959Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 391911). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). 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. 5

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