ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.418G>A (p.Gly140Ser)

gnomAD frequency: 0.00009  dbSNP: rs773857091
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170945 SCV000223505 uncertain significance not provided 2019-12-13 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000533549 SCV000648469 uncertain significance Brugada syndrome 8 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 140 of the HCN4 protein (p.Gly140Ser). This variant is present in population databases (rs773857091, gnomAD 0.02%). 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: 190786). 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.
Fulgent Genetics, Fulgent Genetics RCV000763984 SCV000894935 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000170945 SCV000987627 uncertain significance not provided criteria provided, single submitter clinical testing
Ambry Genetics RCV002326935 SCV002628570 uncertain significance Cardiovascular phenotype 2023-05-09 criteria provided, single submitter clinical testing The p.G140S variant (also known as c.418G>A), located in coding exon 1 of the HCN4 gene, results from a G to A substitution at nucleotide position 418. The glycine at codon 140 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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.

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