ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.73G>A (p.Ala25Thr) (rs200866893)

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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 RCV000720785 SCV000851667 uncertain significance History of neurodevelopmental disorder 2017-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Athena Diagnostics Inc RCV000513738 SCV000841675 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513738 SCV000611000 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513738 SCV000202512 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764694 SCV000895828 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000513738 SCV000240727 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CNTNAP2 gene. The A25T variant has been reported previously in an individual with persistent developmental stuttering; however, the authors concluded that CNTNAP2 variants were not associated with stuttering (Han et al., 2014). The A25T variant is observed in 14/5416 (0.3%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The A25T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin 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 RCV000233751 SCV000289932 uncertain significance Pitt-Hopkins-like syndrome 1 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 25 of the CNTNAP2 protein (p.Ala25Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200866893, ExAC 0.3%). This variant has been reported in individuals with intellectual disability (PMID: 25167861), developmental stuttering (PMID: 24807205), and glioblastoma (PMID: 20711234). ClinVar contains an entry for this variant (Variation ID: 166907). 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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