ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1590G>C (p.Lys530Asn) (rs1555475961)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618670 SCV000738257 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing The c.1590G>C variant (also known as p.K530N), located in coding exon 4 of the HCN4 gene, results from a G to C substitution at nucleotide position 1590. This results in an amino acid substitution of lysine with asparagine at codon 530, an amino acid with similar properties. This nucleotide change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this nucleotide alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. This alteration was reported to segregate with atrial fibrillation in one family in an age dependent manner. In addition, in vitro studies suggested that co-expression of mutant and wild-type channel in HEK-293 cells could affect channel gating (Duhme N et al. Eur. Heart J., 2013 Sep;34:2768-75). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. In addition, this amino acid alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001247767 SCV001421208 uncertain significance Brugada syndrome 8 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 530 of the HCN4 protein (p.Lys530Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 4 of the HCN4 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with tachycardia–bradycardia syndrome and persistent atrial fibrillation (PMID: 23178648). ClinVar contains an entry for this variant (Variation ID: 519553). This variant has been reported to affect HCN4 protein function (PMID: 23178648). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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