ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3379G>A (p.Gly1127Arg)

gnomAD frequency: 0.00003  dbSNP: rs748279911
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550020 SCV000648462 uncertain significance Brugada syndrome 8 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1127 of the HCN4 protein (p.Gly1127Arg). This variant is present in population databases (rs748279911, gnomAD 0.008%). 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: 470667). 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 RCV000995388 SCV001825241 uncertain significance not provided 2019-12-10 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 by another clinical laboratory (ClinVar Variant ID# 470667; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV002456186 SCV002614430 uncertain significance Cardiovascular phenotype 2022-10-14 criteria provided, single submitter clinical testing The p.G1127R variant (also known as c.3379G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3379. The glycine at codon 1127 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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 RCV002476179 SCV002781009 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-11-07 criteria provided, single submitter clinical testing

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