ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3263C>T (p.Ala1088Val)

gnomAD frequency: 0.00004  dbSNP: rs758484576
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001216335 SCV001388126 uncertain significance Brugada syndrome 8 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1088 of the HCN4 protein (p.Ala1088Val). 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: 945650). 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 80%. 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 RCV003163662 SCV003912961 uncertain significance Cardiovascular phenotype 2023-01-30 criteria provided, single submitter clinical testing The p.A1088V variant (also known as c.3263C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3263. The alanine at codon 1088 is replaced by valine, 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.
Dept of Medical Biology, Uskudar University RCV003318397 SCV004022023 uncertain significance Long QT syndrome 2024-01-08 criteria provided, single submitter research Criteria: PM2

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