ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3172T>G (p.Ser1058Ala)

gnomAD frequency: 0.00001  dbSNP: rs1064796786
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480454 SCV000573860 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The S1058A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S1058A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is only conserved in mammals and where alanine is present as the wild type in several non-mammalian species. Finally, in silico analysis suggests that this variant likely does not alter the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV001226827 SCV001399154 uncertain significance Brugada syndrome 8 2024-03-09 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1058 of the HCN4 protein (p.Ser1058Ala). This variant is not present in population databases (gnomAD no frequency). 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: 424082). 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 80%. 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 RCV002323842 SCV002609720 uncertain significance Cardiovascular phenotype 2022-05-14 criteria provided, single submitter clinical testing The p.S1058A variant (also known as c.3172T>G), located in coding exon 8 of the HCN4 gene, results from a T to G substitution at nucleotide position 3172. The serine at codon 1058 is replaced by alanine, an amino acid with similar 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 RCV002506180 SCV002814410 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-08-04 criteria provided, single submitter clinical testing

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