ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2804C>T (p.Ser935Phe) (rs775803239)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223698 SCV000223503 likely benign not specified 2017-12-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726145 SCV000342387 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing
Invitae RCV000473328 SCV000541557 uncertain significance Brugada syndrome 8 2016-04-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 935 of the HCN4 protein (p.Ser935Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 190784). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223698 SCV000280106 uncertain significance not specified 2014-07-30 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. HCN4 p.Ser935Phe Given that the variant is novel, there is a lack of population frequency data, and the gene-phenotype association is unclear, we consider this variant a variant of uncertain significance. To the best of our knowledge the variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign. The serine at codon 935 is not completely conserved across species. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 935 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 29th, 2014). There is also no variation at this codon listed in dbSNP (as of July 29th, 2014).

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