ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3488C>A (p.Pro1163His) (rs756052150)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475375 SCV000541563 uncertain significance Brugada syndrome 8 2019-09-21 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 1163 of the HCN4 protein (p.Pro1163His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs756052150, ExAC 0.01%) but has not been reported in the literature in individuals with a HCN4-related 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000519079 SCV000618191 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The P1163H variant has been reported in a family with atrial fibrillation; however, this family also harbored a variant in the GATA5 gene and detailed segregation information was not provided (Sanz et al., 2018). The P1163H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P1163H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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