Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000703047 | SCV000831928 | uncertain significance | Brugada syndrome 8 | 2023-09-29 | criteria provided, single submitter | clinical testing | 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. 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1102 of the HCN4 protein (p.Arg1102His). 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 missense change has been observed in individual(s) with clinical features of HCN4-related conditions (PMID: 32508047). ClinVar contains an entry for this variant (Variation ID: 579697). |
Fulgent Genetics, |
RCV000763981 | SCV000894932 | uncertain significance | Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002325422 | SCV002605646 | uncertain significance | Cardiovascular phenotype | 2021-07-06 | criteria provided, single submitter | clinical testing | The p.R1102H variant (also known as c.3305G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3305. The arginine at codon 1102 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in a sudden death cohort with micro-ischemia, in an individual who also had another variant in a cardiac related gene (Campuzano O et al. Forensic Sci. Int. 2017 Feb;271:120-125). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other 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. |