ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs548194804
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433991 SCV000535935 uncertain significance not provided 2020-09-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001323315 SCV001514223 uncertain significance Brugada syndrome 8 2023-10-07 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 968 of the HCN4 protein (p.Pro968Leu). This variant is present in population databases (rs548194804, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 392636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function. 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.
Baylor Genetics RCV001323315 SCV003835776 uncertain significance Brugada syndrome 8 2022-10-13 criteria provided, single submitter clinical testing

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