ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.995G>A (p.Arg332Gln) (rs368164073)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622086 SCV000737566 uncertain significance Cardiovascular phenotype 2020-03-09 criteria provided, single submitter clinical testing The p.R332Q variant (also known as c.995G>A), located in coding exon 2 of the HCN4 gene, results from a G to A substitution at nucleotide position 995. The arginine at codon 332 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a cohort referred for arrhythmia or cardiomyopathy genetic testing; however, details were limited (Marschall C. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000995398 SCV001149537 uncertain significance not provided 2020-08-01 criteria provided, single submitter clinical testing
Invitae RCV001374085 SCV001570857 uncertain significance Brugada syndrome 8 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 332 of the HCN4 protein (p.Arg332Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs368164073, ExAC 0.01%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 519261). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Not Available; Align-GVGD: Class C3). 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. 5

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