ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1178G>A (p.Arg393His) (rs786205804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170939 SCV000223499 uncertain significance not provided 2014-06-13 criteria provided, single submitter clinical testing p.Arg393His (CGC>CAC): c.1178 G>A in exon 2 of the HCN4 gene (NM_005477.2). The R393H variant has not been published as a mutation or as a benign polymorphism to our knowledge. The R393H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, this substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense mutation in a nearby residue (L385P) has been reported in association with atrial fibrilation, supporting the functional importance of this region of the protein. Nevertheless, the R393H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV001216458 SCV001388255 uncertain significance Brugada syndrome 8 2019-06-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 393 of the HCN4 protein (p.Arg393His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with sick sinus syndrome (PMID: 28104484). ClinVar contains an entry for this variant (Variation ID: 190780). This variant has been reported to affect HCN4 protein function (PMID: 28104484). 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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