ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.1786G>A (p.Glu596Lys) (rs141064983)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720029 SCV000850904 uncertain significance History of neurodevelopmental disorder 2017-05-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764699 SCV000895833 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000766793 SCV000240771 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing The E596K variant has been previously reported in the heterozygous state in an individual with classic lissencephaly who also had a de novo variant in the KIF2A gene that may have been responsible for the phenotype; additionally, parental testing for the E596K variant in the CNTNAP2 gene was not performed (Cavallin et al., 2016). The E596K variant is observed in 38/66688 (0.06%) alleles from individuals of European background (Lek et al., 2016). The E596K 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000187191 SCV000247055 uncertain significance not specified 2014-07-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000401878 SCV000467253 uncertain significance Pitt-Hopkins-like syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000280573 SCV000467254 uncertain significance Pitt-Hopkins-like syndrome 1 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000280573 SCV000645085 uncertain significance Pitt-Hopkins-like syndrome 1 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 596 of the CNTNAP2 protein (p.Glu596Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs141064983, ExAC 0.06%) but has not been reported in the literature in individuals with a CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205248). 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, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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