ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2495T>C (p.Leu832Pro)

gnomAD frequency: 0.00001  dbSNP: rs1404692878
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002046940 SCV002108842 uncertain significance Brugada syndrome 8 2024-01-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 832 of the HCN4 protein (p.Leu832Pro). 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: 1349438). 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 95%. 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 RCV002425103 SCV002742323 uncertain significance Cardiovascular phenotype 2022-04-19 criteria provided, single submitter clinical testing The p.L832P variant (also known as c.2495T>C), located in coding exon 8 of the HCN4 gene, results from a T to C substitution at nucleotide position 2495. The leucine at codon 832 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002489925 SCV002784008 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-08-03 criteria provided, single submitter clinical testing

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