Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001210981 | SCV001382499 | uncertain significance | Brugada syndrome 8 | 2022-07-18 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs199852438, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the HCN4 protein (p.Arg524Gln). This missense change has been observed in individual(s) with inappropriate sinus tachycardia (PMID: 28182231). ClinVar contains an entry for this variant (Variation ID: 941237). 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. Experimental studies have shown that this missense change affects HCN4 function (PMID: 28182231). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |