Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000622158 | SCV000736215 | uncertain significance | Cardiovascular phenotype | 2016-01-14 | criteria provided, single submitter | clinical testing | The p.G1128S variant (also known as c.3382G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3382. The glycine at codon 1128 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6367 samples (12734 alleles) with coverage at this position. This amino acid position is highly conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. |
Gene |
RCV000658270 | SCV000780041 | uncertain significance | not provided | 2022-04-11 | 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 |
Invitae | RCV001066403 | SCV001231410 | uncertain significance | Brugada syndrome 8 | 2023-09-29 | 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 1128 of the HCN4 protein (p.Gly1128Ser). 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: 518776). 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. |