ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.2147A>G (p.Tyr716Cys)

gnomAD frequency: 0.00002  dbSNP: rs760930032
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725112 SCV000240781 uncertain significance not provided 2012-08-07 criteria provided, single submitter clinical testing p.Tyr716Cys (TAC>TGC):c.2147 A>G in exon 14 of the CNTNAP2 gene (NM_014141.4). The Tyr716Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Tyr716Cys in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Althoug Tyrosine and Cysteine are both uncharged, polar amino acids, the gain of a Cysteine residue could affect disulfide bond formation in the protein. Tyr716Cys alters a position that is well conserved through mammals but is not conserved in more distant species or in related proteins. Some in silico models predict Tyr716Cys may be damaging to protein structure/function, while another model suggests it may not be pathogenic. Therefore, based on the currently available information, it is unclear whether Tyr716Cys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Eurofins Ntd Llc (ga) RCV000725112 SCV000334089 uncertain significance not provided 2015-08-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000644730 SCV000766433 uncertain significance Cortical dysplasia-focal epilepsy syndrome 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 716 of the CNTNAP2 protein (p.Tyr716Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs760930032, ExAC 0.01%). This missense change has been observed in individual(s) with autism spectrum disorder and atypical Rolandic epilepsy (PMID: 18179895, 29358611). ClinVar contains an entry for this variant (Variation ID: 205258). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects CNTNAP2 function (PMID: 22872700, 29788201). 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.
Bioinformatics Core, Luxembourg Center for Systems Biomedicine RCV000656007 SCV000588283 pathogenic Self-limited epilepsy with centrotemporal spikes 2017-01-01 no assertion criteria provided case-control CAADphred>15

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