ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3031T>C (p.Ser1011Pro) (rs890395300)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429781 SCV000535571 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The S1011P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S1011P variant was not observed in approximately 5,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 6X). The S1011P 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.This substitution occurs at a position that is conserved in mammals, however, Proline is the wild-type residue at this position in multiple non-mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV001221790 SCV001393852 uncertain significance Brugada syndrome 8 2019-04-26 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 1011 of the HCN4 protein (p.Ser1011Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 392319). 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: Not Available; Align-GVGD: Class C). 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. 5

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