ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1385G>A (p.Gly462Glu)

gnomAD frequency: 0.00002  dbSNP: rs146714274
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV002266625 SCV002548657 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 2021-07-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003096045 SCV002957805 uncertain significance Brugada syndrome 8 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 462 of the HCN4 protein (p.Gly462Glu). This variant is present in population databases (rs146714274, gnomAD 0.007%). 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: 1696495). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Ambry Genetics RCV004047446 SCV005023672 uncertain significance Cardiovascular phenotype 2023-03-01 criteria provided, single submitter clinical testing The p.G462E variant (also known as c.1385G>A), located in coding exon 4 of the HCN4 gene, results from a G to A substitution at nucleotide position 1385. The glycine at codon 462 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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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