Submissions for variant NM_001323289.2(CDKL5):c.464-2A>G

dbSNP: rs267608480

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002336287	SCV002639898	pathogenic	Inborn genetic diseases	2018-02-19	criteria provided, single submitter	clinical testing	The c.464-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the CDKL5 gene. This mutation (denoted as IVS7-2A>G) was first described in an infant with microcephaly, severe developmental delay, failure to thrive, hand stereotypies, variable tone, and dysmorphic facial features, who met clinical criteria for Rett syndrome but whose features more closely resembled severe epileptic encephalopathy. Amplification of cDNA revealed 2 different RT-PCR products, and sequencing of the smaller product was consistent with loss of exon 8 (coding exon 7) (Evans JC et al. Eur. J. Hum. Genet., 2005 Oct;13:1113-20). This mutation has also been observed in an individual with early onset epileptic encephalopathy (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
RettBASE	RCV000144137	SCV000189214	not provided	not provided		flagged submission	not provided
RettBASE	RCV000170046	SCV000222354	pathogenic	Developmental and epileptic encephalopathy, 2	2014-03-13	no assertion criteria provided	curation	Leads to exon 8 skipping, r.464_554del