ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.196G>A (p.Glu66Lys) (rs786205803)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170937 SCV000223497 uncertain significance not provided 2014-04-15 criteria provided, single submitter clinical testing p.Glu66Lys (GAG>AAG): c.196G>A in exon 1 of the HCN4 gene (NM_005477.2). The E66K variant has not been published as a mutation or as a benign polymorphism to our knowledge. The E66K variant was not observed in approximately 2,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the E66K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. No missense mutations in nearby residues have been reported in association with arrhythmia.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 RCV000808910 SCV000949042 uncertain significance Brugada syndrome 8 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 66 of the HCN4 protein (p.Glu66Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 190778). 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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