ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1571G>A (p.Arg524Gln)

gnomAD frequency: 0.00001  dbSNP: rs199852438
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001210981 SCV001382499 uncertain significance Brugada syndrome 8 2022-07-18 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 941237). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects HCN4 function (PMID: 28182231). 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. This missense change has been observed in individual(s) with inappropriate sinus tachycardia (PMID: 28182231). 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).

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