Submissions for variant NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)

dbSNP: rs267608643

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133327	SCV000191065	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	Reported in association with atypical Rett syndrome and CDKL5-related disorders (Pintaudi et al., 2008; Rademacher et al., 2011; Bahi-Buisson et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29264392, 27599155, 25525159, 19241098, 18063413, 21318334, 29655203, 31313283, 31232219, 33714067, 33436160, 33047306, 35153983, 22678952)
CeGaT Center for Human Genetics Tuebingen	RCV000133327	SCV001246518	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244788	SCV001418032	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143780). This premature translational stop signal has been observed in individuals with clinical features of CDKL5-related conditions (PMID: 18063413, 21318334, 22678952). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg550*) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100).
Undiagnosed Diseases Network, NIH	RCV000170009	SCV002523176	pathogenic	Developmental and epileptic encephalopathy, 2	2021-07-30	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000170009	SCV002559217	pathogenic	Developmental and epileptic encephalopathy, 2		criteria provided, single submitter	clinical testing
3billion	RCV000170009	SCV002572724	pathogenic	Developmental and epileptic encephalopathy, 2	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been previously reported as de novo in a similarly affected individual (PMID: 19241098). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000143780 / PMID: 18063413). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000170009	SCV002766887	pathogenic	Developmental and epileptic encephalopathy, 2	2022-09-02	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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and identified in individuals with epileptic encephalopathy and early-onset seizures in the literature (PMID: PMID:22678952, PMID:18063413, PMID:33436160, PMID:27599155). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
RettBASE	RCV000169916	SCV000188336	pathogenic	Atypical Rett syndrome	2014-03-13	no assertion criteria provided	curation
RettBASE	RCV000170009	SCV000222315	pathogenic	Developmental and epileptic encephalopathy, 2	2014-03-13	no assertion criteria provided	curation