ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.511C>T (p.Arg171Cys)

gnomAD frequency: 0.00004  dbSNP: rs375032955
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000817653 SCV000958230 uncertain significance Cortical dysplasia-focal epilepsy syndrome 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 171 of the CNTNAP2 protein (p.Arg171Cys). This variant is present in population databases (rs375032955, gnomAD 0.008%). This missense change has been observed in individual(s) with childhood apraxia of speech, intellectual disability, and austism spectrum disorder (PMID: 24083349). ClinVar contains an entry for this variant (Variation ID: 660457). 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: "Probably Damaging"; 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.
GeneDx RCV001776033 SCV002012539 uncertain significance not provided 2021-09-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24083349)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265896 SCV002548477 uncertain significance not specified 2023-07-27 criteria provided, single submitter clinical testing Variant summary: CNTNAP2 c.511C>T (p.Arg171Cys) results in a non-conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CNTNAP2 causing Pitt-Hopkins-Like Syndrome 1 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.511C>T has been reported in the literature in one individual affected with childhood apraxia of speech (Worthey_2013). This report does not provide unequivocal conclusions about association of the variant with Pitt-Hopkins-Like Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24083349). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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