ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.896A>G (p.Asn299Ser) (rs1057518303)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414110 SCV000491825 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The N299S variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. Althought the N299S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001325268 SCV001516253 uncertain significance Brugada syndrome 8 2020-09-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 299 of the HCN4 protein (p.Asn299Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 373246). 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 expected to disrupt HCN4 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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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