Submissions for variant NM_001323289.2(CDKL5):c.404-2A>G

dbSNP: rs587783080

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000144742	SCV000190952	pathogenic	not provided	2017-03-15	criteria provided, single submitter	clinical testing	The c.404-2 A>G splice site variant in the CDKL5 gene destroys the canonical splice acceptor site in intron 6 and is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although this pathogenic variant has not been previously reported to our knowledge, other nearby splice site variants have been reported in association with CDKL5-related disorders (RettBASE).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215542	SCV001387293	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2022-08-22	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 16611748, 27081548, 29655203). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 156599). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the CDKL5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593992	SCV005086301	pathogenic	Developmental and epileptic encephalopathy, 2	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 2 (MIM#300672). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity is reported to be dependent on the variant type and position, X-chromosome inactivation in females or post-zygotic mosaicism in males (PMID: 33989939). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The c.404-1G>T canonical splice variant has been classified as pathogenic by GeneDx and RettBASE and has been reported in one individual with a diagnosis of West syndrome (ClinVar; PMID: 16611748). The c.404-1G>A canonical splice variant has been classified as pathogenic by RettBASE and has been reported in individuals with early-onset epileptic encephalopathy (PMIDs: 21309761, 22872100, 27081548). Finally, the c.404-1G>C canonical splice variant was identified in one female with a CDKL5 clinical diagnosis (PMID: 29264392). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by two clinical diagnostic laboratories and has been reported in one Japanese female with early-onset epileptic encephalopathy and a 1-year-old female focal-onset seizure, global developmental delay and other clinical features (ClinVar; PMID: 33436160; DECIPHER). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign