ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1438G>A (p.Gly480Ser)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001246540 SCV001419899 uncertain significance Brugada syndrome 8 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 480 of the HCN4 protein (p.Gly480Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with left ventricular noncompaction (PMID: 28855170). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly480 amino acid residue in HCN4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24569893, 17646576). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254756 SCV001430849 uncertain significance Cardiomyopathy, left ventricular noncompaction 2019-05-07 no assertion criteria provided research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.

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