Submissions for variant NM_014141.6(CNTNAP2):c.1709C>T (p.Ser570Leu)

dbSNP: rs377627481

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513706	SCV000240729	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing	Seen with another variant on the opposite allele (in trans) in a patient with absent corpus callosum in published literature (Cornthwaite et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30567904, 36068917)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513706	SCV000609986	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000644713	SCV000766416	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 570 of the CNTNAP2 protein (p.Ser570Leu). This variant is present in population databases (rs377627481, gnomAD 0.006%). 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: 205215). 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: "Possibly Damaging"; 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.
Fulgent Genetics, Fulgent Genetics	RCV000764698	SCV000895832	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000644713	SCV001322101	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	RCV002517854	SCV003694266	uncertain significance	Inborn genetic diseases	2022-05-26	criteria provided, single submitter	clinical testing	The c.1709C>T (p.S570L) alteration is located in exon 11 (coding exon 11) of the CNTNAP2 gene. This alteration results from a C to T substitution at nucleotide position 1709, causing the serine (S) at amino acid position 570 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003907653	SCV004718175	uncertain significance	CNTNAP2-related condition	2023-10-23	criteria provided, single submitter	clinical testing	The CNTNAP2 c.1709C>T variant is predicted to result in the amino acid substitution p.Ser570Leu. This variant was reported in the compound heterozygous state with another CNTNAP2 missense alteration in a fetus with agenesis of the corpus callosum (Cornthwaite et al. 2022. PubMed ID:36068917). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-147183065-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.