ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2764G>A (p.Asp922Asn)

gnomAD frequency: 0.00002  dbSNP: rs1020318942
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704980 SCV000833957 uncertain significance Brugada syndrome 8 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 922 of the HCN4 protein (p.Asp922Asn). 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: 581221). 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. 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 RCV002440534 SCV002752093 uncertain significance Cardiovascular phenotype 2021-08-19 criteria provided, single submitter clinical testing The p.D922N variant (also known as c.2764G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 2764. The aspartic acid at codon 922 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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