ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2003G>A (p.Arg668Gln) (rs757268783)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439771 SCV000535303 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing The R668Q variant of uncertain significance in the HCN4 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R668Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001238553 SCV001411372 uncertain significance Brugada syndrome 8 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 668 of the HCN4 protein (p.Arg668Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs757268783, ExAC 0.002%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 392090). 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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