Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Biesecker Lab/Clinical Genomics Section, |
RCV000171564 | SCV000055175 | uncertain significance | Ventricular tachycardia | 2018-04-05 | criteria provided, single submitter | research | |
| Invitae | RCV000005485 | SCV002174131 | uncertain significance | Brugada syndrome 8 | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 2 of the HCN4 gene. It does not directly change the encoded amino acid sequence of the HCN4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HCN4 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Brugada syndrome (PMID: 19165230). This variant is also known as c.1209_1209+1insGTGA or IVS2DS. ClinVar contains an entry for this variant (Variation ID: 5177). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19165230). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. |
| Ambry Genetics | RCV002345233 | SCV002651620 | uncertain significance | Cardiovascular phenotype | 2021-07-28 | criteria provided, single submitter | clinical testing | The c.1209+2_1209+3insGAGT intronic variant results from an insertion of 4 nucleotides between positions c.1209+2 and c.1209+3 after coding exon 2 of the HCN4 gene. This variant (also referred to as IVS2DS and c.1209_1209+1insGTGA) has been detected in an individual with symptomatic ventricular tachycardia in whom evaluation revealed features suggestive of Brugada syndrome (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21), and in an individual with bradycardia and intraventricular conduction delay (Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46). A minigene assay suggested this variant may result in aberrantly spliced RT-PCR product in addition to normally spliced product (Ueda K et al. J Hum Genet, 2009 Feb;54:115-21). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| OMIM | RCV000005485 | SCV000025667 | pathogenic | Brugada syndrome 8 | 2009-02-01 | no assertion criteria provided | literature only |