ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2716G>A (p.Gly906Arg)

gnomAD frequency: 0.00001  dbSNP: rs373572497
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000461295 SCV000541558 uncertain significance Brugada syndrome 8 2023-05-10 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 404123). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. 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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 906 of the HCN4 protein (p.Gly906Arg). 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. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852465 SCV000995159 uncertain significance Atrial fibrillation 2018-05-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV002429470 SCV002744303 uncertain significance Cardiovascular phenotype 2021-06-23 criteria provided, single submitter clinical testing The p.G906R variant (also known as c.2716G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 2716. The glycine at codon 906 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002502601 SCV002806908 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2022-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000786320 SCV004039630 uncertain significance not provided 2023-09-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786320 SCV000925095 uncertain significance not provided 2016-08-16 no assertion criteria provided provider interpretation

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