ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.334G>A (p.Gly112Ser)

gnomAD frequency: 0.00002  dbSNP: rs765099391
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457013 SCV000541555 uncertain significance Brugada syndrome 8 2024-01-04 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 112 of the HCN4 protein (p.Gly112Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 404122). 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.
GeneDx RCV001564481 SCV001787656 uncertain significance not provided 2020-09-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 404122; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002323672 SCV002606726 uncertain significance Cardiovascular phenotype 2023-03-06 criteria provided, single submitter clinical testing The p.G112S variant (also known as c.334G>A), located in coding exon 1 of the HCN4 gene, results from a G to A substitution at nucleotide position 334. The glycine at codon 112 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV002481363 SCV002787117 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-10-15 criteria provided, single submitter clinical testing

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