ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.2147A>G (p.Tyr716Cys) (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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725112 SCV000334089 uncertain significance not provided 2015-08-12 criteria provided, single submitter clinical testing
Invitae RCV000644730 SCV000766433 uncertain significance Pitt-Hopkins-like syndrome 1 2018-11-10 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 variant has been reported in an individual with autism spectrum disorder (PMID: 18179895), as well as an individual with atypical Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 205258). Experimental studies have shown that this missense change results in a protein with moderately improper cellular trafficking (PMID: 22872700), but not major trafficking defects (PMID: 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 Rolandic epilepsy 2017-01-01 no assertion criteria provided case-control CAADphred>15

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