ClinVar Genomic variation as it relates to human health
NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)
Variation ID: 143780 Accession: VCV000143780.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp22.13 X: 18604572 (GRCh38) [ NCBI UCSC ] X: 18622692 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 22, 2015 Aug 4, 2024 Oct 1, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001323289.2:c.1648C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001310218.1:p.Arg550Ter nonsense NM_001037343.2:c.1648C>T NP_001032420.1:p.Arg550Ter nonsense NM_001323289.1:c.1648C>T NM_003159.3:c.1648C>T NP_003150.1:p.Arg550Ter nonsense NC_000023.11:g.18604572C>T NC_000023.10:g.18622692C>T NG_008475.1:g.183968C>T - Protein change
- R550*
- Other names
- p.R550*:CGA>TGA
- p.R550*
- Canonical SPDI
- NC_000023.11:18604571:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
CDKL5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1203 | 1967 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2023 | RCV000133327.27 | |
Pathogenic (1) |
no assertion criteria provided
|
Mar 13, 2014 | RCV000169916.3 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 2, 2022 | RCV000170009.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 27, 2023 | RCV001244788.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000191065.15
First in ClinVar: Nov 01, 2014 Last updated: Oct 05, 2023 |
Comment:
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 … (more)
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) (less)
|
|
Pathogenic
(Jun 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 2
Angelman syndrome-like
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001418032.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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). (less)
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246518.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 4
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 2
Affected status: yes
Allele origin:
de novo
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559217.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
Pathogenic
(Jul 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV002523176.2 First in ClinVar: Jun 10, 2022 Last updated: Sep 10, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Seizure (present) , Absent speech (present) , Intellectual disability, severe (present) , Profound global developmental delay (present)
Age: 30-39 years
Sex: female
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572724.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Growth delay (present) , Seizure (present)
|
|
Pathogenic
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 2
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766887.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
|
|
Pathogenic
(Mar 13, 2014)
|
no assertion criteria provided
Method: curation
|
Epileptic encephalopathy, early infantile, 2
Affected status: yes
Allele origin:
unknown
|
RettBASE
Accession: SCV000222315.1
First in ClinVar: Apr 24, 2015 Last updated: Apr 24, 2015 |
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Not Rett syndrome - early-onset seizures and mental retardation
Method: not specified, MECP2 negative
|
|
Pathogenic
(Mar 13, 2014)
|
no assertion criteria provided
Method: curation
|
Atypical Rett syndrome
Affected status: yes
Allele origin:
de novo
|
RettBASE
Accession: SCV000188336.2
First in ClinVar: Aug 17, 2014 Last updated: Apr 22, 2015 |
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - early-onset seizure
Method: direct, not certain
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants. | Kobayashi Y | Brain & development | 2021 | PMID: 33436160 |
CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature. | Lilles S | Neuropediatrics | 2016 | PMID: 27599155 |
The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. | Fehr S | European journal of human genetics : EJHG | 2013 | PMID: 22872100 |
Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. | Bahi-Buisson N | American journal of medical genetics. Part A | 2012 | PMID: 22678952 |
Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. | Rademacher N | Neurogenetics | 2011 | PMID: 21318334 |
Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. | Russo S | Neurogenetics | 2009 | PMID: 19241098 |
Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. | Pintaudi M | Epilepsy & behavior : E&B | 2008 | PMID: 18063413 |
Text-mined citations for rs267608643 ...
HelpRecord last updated Aug 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.