ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3353T>C (p.Leu1118Pro)

gnomAD frequency: 0.00010  dbSNP: rs1165134160
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647246 SCV000769035 uncertain significance Brugada syndrome 8 2017-10-03 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with HCN4-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces leucine with proline at codon 1118 of the HCN4 protein (p.Leu1118Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline.

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