ClinVar Miner

Submissions for variant NM_014141.6(CNTNAP2):c.2650C>T (p.Arg884Trp)

gnomAD frequency: 0.00001  dbSNP: rs373383452
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187215 SCV000240797 uncertain significance not provided 2013-01-11 criteria provided, single submitter clinical testing p.Arg884Trp (CGG>TGG): c.2650 C>T in exon 17 of the CNTNAP2 gene (NM_014141.4). The Arg884Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged, non-polar Tryptophan residue. It alters a conserved position in the third laminin G-like domain; however, missense mutations have not been reported in this region of the gene in association with epilepsy. Multiple in silico algorithms predict Arg884Trp may be damaging to protein structure/function, although another model suggests it may be benign. Therefore, based on the currently available information, it is unclear whether Arg884Trp is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001852450 SCV002219538 uncertain significance Cortical dysplasia-focal epilepsy syndrome 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 884 of the CNTNAP2 protein (p.Arg884Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373383452, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 205270). 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. 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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