ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2903C>T (p.Pro968Leu) (rs548194804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433991 SCV000535935 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The P968L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/20022 (0.02%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the P968L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Invitae RCV001323315 SCV001514223 uncertain significance Brugada syndrome 8 2020-07-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 968 of the HCN4 protein (p.Pro968Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs548194804, ExAC 0.02%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 392636). 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.

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