ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3414del (p.Arg1140fs) (rs746402732)

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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 RCV000621990 SCV000736407 uncertain significance Cardiovascular phenotype 2017-02-15 criteria provided, single submitter clinical testing <p style="text-align:justify">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 frameshift occurs in the last exon of HCN4, and is not expected to trigger nonsense-mediated mRNA decay. Rather, this alteration results in truncation and loss of the C-terminal 64 amino acids of the HCN4 protein, and the exact functional impact of the loss of these amino acids is unknown at this time. 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 2019-12-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HCN4 gene (p.Arg1140Glyfs*41). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acids of the HCN4 protein. This variant is present in population databases (rs746402732, ExAC 0.02%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 518849). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) 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.

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