Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000621990 | SCV000736407 | uncertain significance | Cardiovascular phenotype | 2022-02-23 | criteria provided, single submitter | clinical testing | The c.3414delT variant, located in coding exon 8 of the HCN4 gene, results from a deletion of one nucleotide at nucleotide position 3414, causing a translational frameshift with a predicted alternate stop codon (p.R1140Gfs*41). This alteration occurs at the 3' terminus of the HCN4 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 64 amino acids of the protein. The exact functional effect of this alteration is unknown. Frameshift variants are typically deleterious in nature. However, loss of function through HCN4 protein truncation has not been clearly established as a mechanism of disease. Prior studies reporting HCN4 frameshift and splice alterations did not demonstrate that channel truncation was truly pathogenic in the patients in whom the sequence alterations were identified (Ueda K et al. J. Hum. Genet., 2009 Feb;54:115-21; Schweizer PA et al. Circ Arrhythm Electrophysiol, 2010 Oct;3:542-52; Schulze-Bahr E et al. J. Clin. Invest., 2003 May;111:1537-45). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001059075 | SCV001223681 | uncertain significance | Brugada syndrome 8 | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg1140Glyfs*41) in the HCN4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the HCN4 protein. This variant is present in population databases (rs746402732, gnomAD 0.01%). 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: 518849). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. |
| Ai |
RCV002223230 | SCV002501062 | uncertain significance | not provided | 2022-01-06 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV002223230 | SCV003810702 | uncertain significance | not provided | 2020-05-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV002223230 | SCV004023842 | uncertain significance | not provided | 2023-02-06 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease |