ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2807C>T (p.Pro936Leu)

gnomAD frequency: 0.00002  dbSNP: rs769959023
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001223993 SCV001396164 uncertain significance Brugada syndrome 8 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 936 of the HCN4 protein (p.Pro936Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 951977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002436872 SCV002745805 uncertain significance Cardiovascular phenotype 2020-07-22 criteria provided, single submitter clinical testing The p.P936L variant (also known as c.2807C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2807. The proline at codon 936 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available 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.
Fulgent Genetics, Fulgent Genetics RCV002497764 SCV002812906 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-09-02 criteria provided, single submitter clinical testing

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