Submissions for variant NM_001323289.2(CDKL5):c.578A>T (p.Asp193Val)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003112433	SCV003787197	likely pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 193 of the CDKL5 protein (p.Asp193Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CDKL5-related conditions (PMID: 30898514). ClinVar contains an entry for this variant (Variation ID: 2419189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function with a positive predictive value of 95%. This variant disrupts the p.Asp193 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.