ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1005G>A (p.Met335Ile)

gnomAD frequency: 0.00003  dbSNP: rs758797709
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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 RCV000542848 SCV000648430 uncertain significance Brugada syndrome 8 2025-01-15 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 335 of the HCN4 protein (p.Met335Ile). This variant is present in population databases (rs758797709, gnomAD 0.007%). 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: 470643). 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) 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 RCV000620654 SCV000737534 uncertain significance Cardiovascular phenotype 2024-08-19 criteria provided, single submitter clinical testing The c.1005G>A (p.M335I) alteration is located in exon 2 (coding exon 2) of the HCN4 gene. This alteration results from a G to A substitution at nucleotide position 1005, causing the methionine (M) at amino acid position 335 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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