ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3172T>G (p.Ser1058Ala) (rs1064796786)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480454 SCV000573860 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The S1058A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S1058A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is only conserved in mammals and where alanine is present as the wild type in several non-mammalian species. Finally, in silico analysis suggests that this variant likely does not alter the protein structure/function.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000480454 SCV001149522 uncertain significance not provided 2018-12-01 criteria provided, single submitter clinical testing
Invitae RCV001226827 SCV001399154 uncertain significance Brugada syndrome 8 2019-08-30 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 1058 of the HCN4 protein (p.Ser1058Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 424082). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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