Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000483093 | SCV000570506 | uncertain significance | not provided | 2016-06-01 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the CNTNAP2 gene. The G228R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G228R 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. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV001851204 | SCV002227917 | uncertain significance | Cortical dysplasia-focal epilepsy syndrome | 2022-10-05 | criteria provided, single submitter | clinical testing | 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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 421332). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. This variant is present in population databases (rs371512835, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 228 of the CNTNAP2 protein (p.Gly228Arg). |
Escayg Lab, |
RCV001553785 | SCV001478474 | uncertain significance | Autism spectrum disorder; Epilepsy; Intellectual disability | no assertion criteria provided | research | The Gly228Arg variant in CNTNAP2 was identified in a Pakistani family with epilepsy, intellectual disability and autism spectrum disorder and segregated with disease in all sequenced individuals. It is a non-conservative amino substitution and absent from gnomAD in a homozygous state. Conflicting predictions (CADD: "21.4", PolyPhen-2: "Probably Damaging", SIFT: "Tolerated", PROVEAN: "Deleterious") and lack of previous homozygous pathogenic missense variants in CNTNAP2 in association with disease status leave the clinical significance of this variant unknown. |