ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1447C>T (p.Arg483Trp)

gnomAD frequency: 0.00001  dbSNP: rs1304145729
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001320340 SCV001511122 uncertain significance Brugada syndrome 8 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 483 of the HCN4 protein (p.Arg483Trp). 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. 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. ClinVar contains an entry for this variant (Variation ID: 1020717). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%).
Ambry Genetics RCV002395696 SCV002700794 uncertain significance Cardiovascular phenotype 2019-10-17 criteria provided, single submitter clinical testing The p.R483W variant (also known as c.1447C>T), located in coding exon 4 of the HCN4 gene, results from a C to T substitution at nucleotide position 1447. The arginine at codon 483 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002476500 SCV002791214 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-08-30 criteria provided, single submitter clinical testing

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