ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.2242G>T (p.Asp748Tyr) (rs371691712)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724077 SCV000226131 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing
GeneDx RCV000724077 SCV000240786 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing The D748Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D748Y variant is observed in 22/18746 (0.1%) alleles from individuals of East Asian background (Lek et al., 2016). The D748Y 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, and in silico analysis predicts this variant is probably 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 RCV000468497 SCV000553436 uncertain significance Pitt-Hopkins-like syndrome 1 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 748 of the CNTNAP2 protein (p.Asp748Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs371691712, ExAC 0.2%). This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 194401). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genetic Services Laboratory,University of Chicago RCV000187205 SCV000594182 uncertain significance not specified 2016-06-24 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767938 SCV000898623 uncertain significance Autism 15; Pitt-Hopkins-like syndrome 1 2018-07-31 criteria provided, single submitter clinical testing CNTNAP2 NM_014141.5 exon 14 p.Asp748Tyr (c.2242G>T): This variant has not been reported in the literature but is present in 0.1% (22/18746) of East Asian alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:194401). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000468497 SCV001326085 uncertain significance Pitt-Hopkins-like syndrome 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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