ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3596T>A (p.Leu1199Gln)

gnomAD frequency: 0.00004  dbSNP: rs146751122
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000596045 SCV000709199 uncertain significance not provided 2017-06-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000647248 SCV000769037 uncertain significance Brugada syndrome 8 2024-06-11 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1199 of the HCN4 protein (p.Leu1199Gln). This variant is present in population databases (rs146751122, gnomAD 0.008%). 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: 502460). 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.
GeneDx RCV000596045 SCV002562306 uncertain significance not provided 2022-02-15 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002456314 SCV002614907 uncertain significance Cardiovascular phenotype 2021-04-08 criteria provided, single submitter clinical testing The p.L1199Q variant (also known as c.3596T>A), located in coding exon 8 of the HCN4 gene, results from a T to A substitution at nucleotide position 3596. The leucine at codon 1199 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. 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.

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