ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2833C>T (p.Pro945Ser)

gnomAD frequency: 0.00002  dbSNP: rs778739758
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001244410 SCV001417630 uncertain significance Brugada syndrome 8 2022-03-08 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 945 of the HCN4 protein (p.Pro945Ser). This variant is present in population databases (rs778739758, gnomAD 0.007%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 24607718). ClinVar contains an entry for this variant (Variation ID: 969135). 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. Experimental studies have shown that this missense change does not substantially affect HCN4 function (PMID: 24607718). 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 RCV002436962 SCV002746484 uncertain significance Cardiovascular phenotype 2022-06-13 criteria provided, single submitter clinical testing The p.P945S variant (also known as c.2833C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2833. The proline at codon 945 is replaced by serine, an amino acid with similar properties. This altertaion was reported in an atrial fibrillation cohort and the authors noted this alteration may have an impact on protein function (Macri V et al. Heart Rhythm, 2014 Jun;11:1055-1062). This amino acid position is poorly conserved in available vertebrate species. 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.
Fulgent Genetics, Fulgent Genetics RCV002491817 SCV002803223 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-11-20 criteria provided, single submitter clinical testing

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