ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2398C>T (p.Arg800Cys)

gnomAD frequency: 0.00004  dbSNP: rs181894662
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000811194 SCV000951448 uncertain significance Brugada syndrome 8 2024-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 800 of the HCN4 protein (p.Arg800Cys). This variant is present in population databases (rs181894662, gnomAD 0.008%). 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: 655088). 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 with a negative predictive value of 95%. 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.
Ambry Genetics RCV002453832 SCV002738493 uncertain significance Cardiovascular phenotype 2021-08-26 criteria provided, single submitter clinical testing The p.R800C variant (also known as c.2398C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2398. The arginine at codon 800 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002478880 SCV002787869 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-08-05 criteria provided, single submitter clinical testing

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