Submissions for variant NM_001323289.2(CDKL5):c.175C>T (p.Arg59Ter)

dbSNP: rs62653623

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145523	SCV000192611	pathogenic	Developmental and epileptic encephalopathy, 2	2013-02-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711154	SCV000841484	pathogenic	not provided	2018-05-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385702	SCV001585662	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-02-03	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: 143783). This premature translational stop signal has been observed in individual(s) with CDKL5-related conditions (PMID: 16611748, 23583054, 31313283). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg59*) 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).
GeneDx	RCV000711154	SCV001766013	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a female with epileptic encephalopathy and severe intellectual disability (PMID: 16611748), and in heterozygous state in a female with severe intellectual disability, hand stereotypies, and deceleration of head growth (PMID: 22678952); 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; Published functional studies demonstrate a damaging effect, with mouse models exhibiting autistic-like behaviors (PMID: 31201320, 30952813); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20493745, 21502606, 23238081, 29455050, 23583054, 19740913, 29961513, 31232219, 30952813, 31539537, 31456437, 31313283, 33905871, 33047306, 22678952, 16611748, 31201320)
Centre for Population Genomics, CPG	RCV004724847	SCV005335347	pathogenic	CDKL5 disorder	2024-08-21	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4). PMID 16611748 ClinVar Variation ID: 143783
RettBASE	RCV000145523	SCV000188339	pathogenic	Developmental and epileptic encephalopathy, 2	2014-03-13	no assertion criteria provided	curation	In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles
RettBASE	RCV000170010	SCV000222317	pathogenic	Atypical Rett syndrome	2014-03-13	no assertion criteria provided	curation	In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles
PreventionGenetics, part of Exact Sciences	RCV004532618	SCV004723842	pathogenic	CDKL5-related disorder	2024-02-01	no assertion criteria provided	clinical testing	The CDKL5 c.175C>T variant is predicted to result in premature protein termination (p.Arg59*). This variant has been reported in multiple male and female individuals with developmental and epileptic encephalopathy and in all patients where parents were available for testing the variant was reported to be de novo (Archer et al. 2006. PubMed ID: 16611748; Castrén et al. 2010. PubMed ID: 20493745; Klein et al. 2011. PubMed ID: 21502606; Bahi-Buisson et al. 2012. PubMed ID: 22678952; Mirzaa et al. 2013. PubMed ID: 23583054; Almomen et al. 2018. PubMed ID: 29961513). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CDKL5 are expected to be pathogenic. This variant is interpreted as pathogenic.