ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1297G>A (p.Gly433Ser)

gnomAD frequency: 0.00001  dbSNP: rs573588965
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544788 SCV000648433 uncertain significance Brugada syndrome 8 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 433 of the HCN4 protein (p.Gly433Ser). This variant is present in population databases (rs573588965, gnomAD 0.004%). 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: 470646). 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 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.
Fulgent Genetics, Fulgent Genetics RCV000763983 SCV000894934 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV002223872 SCV002502521 uncertain significance not provided 2021-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002384192 SCV002691388 uncertain significance Cardiovascular phenotype 2021-12-03 criteria provided, single submitter clinical testing The p.G433S variant (also known as c.1297G>A), located in coding exon 3 of the HCN4 gene, results from a G to A substitution at nucleotide position 1297. The glycine at codon 433 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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