Submissions for variant NM_014141.6(CNTNAP2):c.1861C>A (p.Pro621Thr)

dbSNP: rs779028422

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187264	SCV000240846	uncertain significance	not provided	2015-11-10	criteria provided, single submitter	clinical testing	p.Pro621Thr (CCT>ACT): c.1861 C>A in exon 12 of the CNTNAP2 gene (NM_014141.5). The P621T 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 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P621T 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species, and Threonine is observed at this position in other species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001350070	SCV001544443	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 621 of the CNTNAP2 protein (p.Pro621Thr). This variant is present in population databases (rs779028422, gnomAD 0.0009%). 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: 205313). 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"). 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.
PreventionGenetics, part of Exact Sciences	RCV004748645	SCV005355501	uncertain significance	CNTNAP2-related disorder	2024-09-07	no assertion criteria provided	clinical testing	The CNTNAP2 c.1861C>A variant is predicted to result in the amino acid substitution p.Pro621Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.