Submissions for variant NM_014141.6(CNTNAP2):c.3922_3970dup (p.Glu1324delinsGlyArgArgHisHisGluGlnArgProGlnLeuHisArgAspHisTer)

dbSNP: rs757043221

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523722	SCV000620203	uncertain significance	not provided	2017-08-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CNTNAP2 gene. The c.3922_3970dup49 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3922_3970dup49 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.3922_3970dup49 variant causes a frameshift starting with codon Glutamic acid 1324, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Glu1324GlyfsX16. This variant is predicted to cause loss of normal protein function either through protein truncation as the last 8 amino acid residues are replaced with 15 aberrant residues; however, loss-of-function variants have not been reported downstream of this position in the protein.
Invitae	RCV001053103	SCV001217345	likely pathogenic	Cortical dysplasia-focal epilepsy syndrome	2021-07-29	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the CNTNAP2 gene (p.Glu1324Glyfs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the CNTNAP2 protein and extend the protein by 7 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This frameshift has been observed in individual(s) with clinical features of CNTNAP2-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 451490). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.