ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3262G>A (p.Ala1088Thr)

gnomAD frequency: 0.00004  dbSNP: rs1050326641
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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 RCV000536030 SCV000648458 uncertain significance Brugada syndrome 8 2024-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1088 of the HCN4 protein (p.Ala1088Thr). 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 missense change has been observed in individual(s) with unexplained cardiac arrest (PMID: 35352813). ClinVar contains an entry for this variant (Variation ID: 470664). 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852464 SCV000995158 uncertain significance Cardiomyopathy 2019-01-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV004024150 SCV005023686 uncertain significance Cardiovascular phenotype 2023-11-28 criteria provided, single submitter clinical testing The p.A1088T variant (also known as c.3262G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3262. The alanine at codon 1088 is replaced by threonine, 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.

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