NM_001323289.2(CDKL5):c.1247_1248del (p.Glu416fs) AND CDKL5 disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 26, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001507057.5

Allele description [Variation Report for NM_001323289.2(CDKL5):c.1247_1248del (p.Glu416fs)]

NM_001323289.2(CDKL5):c.1247_1248del (p.Glu416fs)

Gene:

CDKL5:cyclin dependent kinase like 5 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

Xp22.13

Genomic location:

Preferred name:

NM_001323289.2(CDKL5):c.1247_1248del (p.Glu416fs)

Other names:

NM_001323289.2(CDKL5):c.1247_1248del; p.Glu416fs

HGVS:

NC_000023.11:g.18604169AG[1]
NG_008475.1:g.183565AG[1]
NM_001037343.2:c.1247_1248del
NM_001323289.2:c.1247_1248delMANE SELECT
NM_003159.3:c.1247_1248del
NP_001032420.1:p.Glu416fs
NP_001310218.1:p.Glu416fs
NP_003150.1:p.Glu416fs
NC_000023.10:g.18622289AG[1]
NC_000023.10:g.18622289_18622290del
NC_000023.11:g.18604171_18604172delAG
NM_003159.2(CDKL5):c.1247_1248delAG
NM_003159.2:c.1247_1248delAG
p.Glu416Valfs

Protein change:

E416fs

Links:

dbSNP: rs786204967

NCBI 1000 Genomes Browser:

rs786204967

Molecular consequence:

NM_001037343.2:c.1247_1248del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001323289.2:c.1247_1248del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003159.3:c.1247_1248del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: CDKL5 disorder
Identifiers:: MONDO: MONDO:0100039; MedGen: CN296942

Recent activity

Clear Turn Off Turn On

Homo sapiens large subunit GTPase 1 homolog (S. cerevisiae), mRNA (cDNA clone MG...
Homo sapiens large subunit GTPase 1 homolog (S. cerevisiae), mRNA (cDNA clone MGC:87237 IMAGE:30343878), complete cds
gi|46329580|gb|BC068500.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001712024	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V1)	Pathogenic (Mar 26, 2021)	germline	curation	Citation Link,
SCV005335209	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Sep 18, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001712024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V1)

Pathogenic
(Mar 26, 2021)

germline

curation

Citation Link,

SCV005335209

Centre for Population Genomics, CPG

criteria provided, single submitter

(McKnight et al. (Hum Mutat. 2022))

Pathogenic
(Sep 18, 2024)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.

McKnight D, Bean L, Karbassi I, Beattie K, Bienvenu T, Bonin H, Fang P, Chrisodoulou J, Friez M, Helgeson M, Krishnaraj R, Meng L, Mighion L, Neul J, Percy A, Ramsden S, Zoghbi H, Das S.

Hum Mutat. 2022 Aug;43(8):1097-1113. doi: 10.1002/humu.24302. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34837432
PMCID:: PMC9135956

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV001712024.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID: 27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, PM2_supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Population Genomics, CPG, SCV005335209.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

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). Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4). PMID: 22872100, PMID: 23064044,PMID: 27779742, PMID: 30945278, PMID: 31164858, Variation ID: 189554 This variant is absent from gnomAD v4 (PM2_Supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine