ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.2047G>A (p.Glu683Lys) (rs372580822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720374 SCV000851251 uncertain significance History of neurodevelopmental disorder 2016-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000187198 SCV000240778 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing The E683K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E683K 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 across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000696952 SCV000825537 uncertain significance Pitt-Hopkins-like syndrome 1 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 683 of the CNTNAP2 protein (p.Glu683Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs372580822, ExAC 0.02%). This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205255). 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 C0"). 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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