ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.3758T>C (p.Ile1253Thr) (rs767821521)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000717284 SCV000848133 uncertain significance History of neurodevelopmental disorder 2016-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000515288 SCV000611465 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000766802 SCV000240852 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CNTNAP2 gene. The I1253T missensechange was previously identified in two siblings with an autism spectrum disorder but was also detected in another sibling and their mother who were reported to be unaffected (Bakkaloglu et al., 2008). Functional studies suggest that the I1253T variant does not impact the cellular trafficking of theCNTNAP2 protein (Falivelli et al., 2012). The I1253T variant is observed in 48/34420 (0.14%)alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). TheI1253T 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 RCV000187270 SCV000247067 uncertain significance not specified 2014-09-17 criteria provided, single submitter clinical testing
Invitae RCV000644724 SCV000766427 uncertain significance Pitt-Hopkins-like syndrome 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1253 of the CNTNAP2 protein (p.Ile1253Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs767821521, ExAC 0.09%). This variant has been reported in the literature in a family affected with autism spectrum disorders (PMID: 18179895). ClinVar contains an entry for this variant (Variation ID: 205319). Experimental studies have shown that this missense change does not interrupt the subcellular localization of CNTNAP2 protein (PMID: 22872700). 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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