ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3220C>T (p.Leu1074Phe)

gnomAD frequency: 0.00012  dbSNP: rs200399862
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001065763 SCV001230746 uncertain significance Brugada syndrome 8 2024-11-24 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1074 of the HCN4 protein (p.Leu1074Phe). This variant is present in population databases (rs200399862, gnomAD 0.01%). 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: 859608). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HCN4 protein function. 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 RCV002320332 SCV002609959 uncertain significance Cardiovascular phenotype 2021-12-23 criteria provided, single submitter clinical testing The p.L1074F variant (also known as c.3220C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3220. The leucine at codon 1074 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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