Submissions for variant NM_014141.6(CNTNAP2):c.37C>T (p.Leu13Phe)

gnomAD frequency: 0.00001  dbSNP: rs796052375

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187183	SCV000240763	uncertain significance	not provided	2013-10-18	criteria provided, single submitter	clinical testing	p.Leu13Phe (CTC>TTC): c.37 C>T in exon 1 of the CNTNAP2 gene (NM_014141.5). The L13F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the L13F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species, and Phenylalanine has been seen at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, L13F is likely a benign variant but the possibility that it is a pathogenic mutation cannot be completely excluded. The variant is found in INFANT-EPI,EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690704	SCV000818404	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2018-03-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 13 of the CNTNAP2 protein (p.Leu13Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205242). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Illumina Laboratory Services, Illumina	RCV000690704	SCV001325870	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002513995	SCV003676031	uncertain significance	Inborn genetic diseases	2022-08-17	criteria provided, single submitter	clinical testing	The c.37C>T (p.L13F) alteration is located in exon 1 (coding exon 1) of the CNTNAP2 gene. This alteration results from a C to T substitution at nucleotide position 37, causing the leucine (L) at amino acid position 13 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.