ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1657G>A (p.Asp553Asn)

gnomAD frequency: 0.00001  dbSNP: rs104894485
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000005483 SCV001273992 uncertain significance Sick sinus syndrome 2, autosomal dominant 2017-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001851666 SCV002187313 uncertain significance Brugada syndrome 8 2022-04-06 criteria provided, single submitter clinical testing 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HCN4 function (PMID: 15123648, 19748888, 23075627). 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. ClinVar contains an entry for this variant (Variation ID: 5175). This missense change has been observed in individual(s) with bradycardia and/or prolonged QT interval (PMID: 15123648). This variant is present in population databases (rs104894485, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 553 of the HCN4 protein (p.Asp553Asn).
OMIM RCV000005483 SCV000025665 pathogenic Sick sinus syndrome 2, autosomal dominant 2004-06-25 no assertion criteria provided literature only

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