Submissions for variant NM_014141.6(CNTNAP2):c.2497del (p.Trp833fs)

gnomAD frequency: 0.00001  dbSNP: rs1391540245

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644701	SCV000766404	pathogenic	Cortical dysplasia-focal epilepsy syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp833Glyfs*18) in the CNTNAP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNTNAP2 are known to be pathogenic (PMID: 19896112, 21827697, 25045150, 26843181, 27439707). This variant is not present in population databases (gnomAD no frequency). 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: 536312). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001541691	SCV001759718	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV000644701	SCV002548923	likely pathogenic	Cortical dysplasia-focal epilepsy syndrome	2021-05-27	criteria provided, single submitter	clinical testing	The homozygous c.2497del (p.Trp833GlyfsTer18) variant identified in the CNTNAP2 gene is the deletion of a single nucleotide resulting in the frameshift of the protein at amino acid 833/1332 (exon 16/24). This variant is found with low frequency in gnomAD(v3.1.1) (2 heterozygotes, 0 homozygotes; allelefrequency:1.31e-5) suggesting it is not a common benign variant in the populations represented in that database. The c.2497del (p.Trp833GlyfsTer18) variant isreported in ClinVar as Pathogenic (VarID:536312) and to our current knowledge has not been reported in affected individuals in the literature, although nonsense and frameshift variants downstream of this one have been reported in affected individuals [PMID:27439707]. Given its deleterious nature and absence in population databases, the homozygous c.2497del (p.Trp833GlyfsTer18) variant identified in the CNTNAP2 gene is reported as Likely Pathogenic.
Ambry Genetics	RCV002424472	SCV002741071	pathogenic	Inborn genetic diseases	2019-03-23	criteria provided, single submitter	clinical testing	The c.2497delT pathogenic mutation, located in coding exon 16 of the CNTNAP2 gene, results from a deletion of one nucleotide at nucleotide position 2497, causing a translational frameshift with a predicted alternate stop codon (p.W833Gfs*18). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.