ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1132C>T (p.Arg378Cys) (rs758468167)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170938 SCV000223498 uncertain significance not provided 2014-05-01 criteria provided, single submitter clinical testing p.Arg378Cys (CGC>TGC): c.1132 C>T in exon 2 of the HCN4 gene (NM_005477.2). To our knowledge, the R378C variant has not been published as a mutation or as a benign polymorphism. The R378C 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. The R378C 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. 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. However, no definitely disease-causing mutations in nearby residues have been reported in association with Brugada syndrome. 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).
Ambry Genetics RCV000619663 SCV000737997 uncertain significance Cardiovascular phenotype 2017-05-04 criteria provided, single submitter clinical testing The p.R378C variant (also known as c.1132C>T), located in coding exon 2 of the HCN4 gene, results from a C to T substitution at nucleotide position 1132. The arginine at codon 378 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001051690 SCV001215858 uncertain significance Brugada syndrome 8 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 378 of the HCN4 protein (p.Arg378Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs758468167, ExAC 0.03%). This variant has been observed in individual(s) with sick sinus syndrome (PMID: 30196304). ClinVar contains an entry for this variant (Variation ID: 190779). This variant has been reported to affect HCN4 protein function (PMID: 30196304). 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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