This variant is interpreted as a Likely pathogenic for Epileptic encephalopathy, early infantile, 67, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate : PS4 downgraded in strength to Moderate (Variant absent from controls and recurrent in multiple unrelated patients PMID:28628100,23020937,29630738,29795476). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6-Strong : PM6 upgraded in strength to Strong (Assumed de novo in multiple unrelated patients PMID:28628100,23020937,29630738,29795476).
ClinVar Genomic variation as it relates to human health
NM_015267.4(CUX2):c.1768G>A (p.Glu590Lys)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015267.4(CUX2):c.1768G>A (p.Glu590Lys)
Variation ID: 585015 Accession: VCV000585015.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.12 12: 111310550 (GRCh38) [ NCBI UCSC ] 12: 111748354 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 25, 2018 Oct 8, 2024 Sep 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015267.4:c.1768G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056082.2:p.Glu590Lys missense NM_001370598.1:c.1582G>A NP_001357527.1:p.Glu528Lys missense NC_000012.12:g.111310550G>A NC_000012.11:g.111748354G>A NG_023039.2:g.281527G>A - Protein change
- E590K, E528K
- Other names
- -
- Canonical SPDI
- NC_000012.12:111310549:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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. |
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| CUX2 | - | - |
GRCh38 GRCh37 |
299 | 307 | |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2023 | RCV000709621.12 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 26, 2024 | RCV001662782.3 | |
|
CUX2-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 29, 2022 | RCV003420268.4 |
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. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(May 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 67
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890027.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
|
|
|
Likely pathogenic
(Feb 27, 2019)
|
criteria provided, single submitter
Method: curation
|
Developmental and epileptic encephalopathy, 67
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000930060.1
First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
Comment:
This variant is interpreted as a Likely pathogenic for Epileptic encephalopathy, early infantile, 67, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent … (more)
This variant is interpreted as a Likely pathogenic for Epileptic encephalopathy, early infantile, 67, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate : PS4 downgraded in strength to Moderate (Variant absent from controls and recurrent in multiple unrelated patients PMID:28628100,23020937,29630738,29795476). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6-Strong : PM6 upgraded in strength to Strong (Assumed de novo in multiple unrelated patients PMID:28628100,23020937,29630738,29795476). (less)
|
|
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Pathogenic
(Sep 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 67
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835539.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
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Pathogenic
(Jul 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 67
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004022283.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Clinical Features:
Seizure (present) , Global developmental delay (present) , Bilateral tonic-clonic seizure (present) , Bilateral tonic-clonic seizure on awakening (present) , Tonic seizure (present) , Epileptic … (more)
Seizure (present) , Global developmental delay (present) , Bilateral tonic-clonic seizure (present) , Bilateral tonic-clonic seizure on awakening (present) , Tonic seizure (present) , Epileptic encephalopathy (present) (less)
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Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
CUX2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004115796.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CUX2 c.1768G>A variant is predicted to result in the amino acid substitution p.Glu590Lys. This variant has been repeatedly reported to occur de novo in … (more)
The CUX2 c.1768G>A variant is predicted to result in the amino acid substitution p.Glu590Lys. This variant has been repeatedly reported to occur de novo in individuals with nonsyndromic intellectual disability (see for example at Rauch et al. 2012. PubMed ID: 23020937, described as chr12: g.111748354G>A at Table 4 and Supplementary Table S2 & S8; Kosmicki et al. 2017. PubMed ID: 28191890, Supplementary Table 2; Geisheker et al. 2017. PubMed ID: 28628100, Suppl. Table 4; Iwama et al. 2019. PubMed ID: 30842224). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001874933.2
First in ClinVar: Sep 19, 2021 Last updated: Oct 08, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 34758253, 23020937, 28191890, 30842224, 24866042, 29630738, 28628100, 29795476) (less)
|
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Pathogenic
(Nov 24, 2020)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 67
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000839537.4
First in ClinVar: Oct 10, 2018 Last updated: Nov 28, 2020 |
Comment on evidence:
In 9 unrelated patients with developmental and epileptic encephalopathy-67 (DEE67; 618141), Chatron et al. (2018) identified the same de novo heterozygous c.1768G-A transition (c.1768G-A, NM_015267.3) … (more)
In 9 unrelated patients with developmental and epileptic encephalopathy-67 (DEE67; 618141), Chatron et al. (2018) identified the same de novo heterozygous c.1768G-A transition (c.1768G-A, NM_015267.3) in the CUX2 gene, resulting in a glu590-to-lys (E590K) substitution at a highly conserved residue in the third alpha helix of the first DNA-binding CUT domain. The mutation, which was found by exome sequencing, was not found in the ExAC or gnomAD databases. Three of the patients had previously been reported. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of refractory infantile spasms or myoclonic or absence seizures in the first months of life. In a 17-year-old Danish girl with DEE67, Barington et al. (2018) identified a de novo heterozygous E590K mutation in the CUX2 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient had global developmental delay from infancy and developed myoclonic and generalized seizures at 12 months of age. (less)
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|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy, 67
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760294.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
|
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Pathogenic
(Apr 12, 2021)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
de novo
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Molecular Genetics laboratory, Necker Hospital
Accession: SCV004031380.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Clinical Features:
Intellectual disability (present)
|
Comment:
Comment:
The CUX2 c.1768G>A variant is predicted to result in the amino acid substitution p.Glu590Lys. This variant has been repeatedly reported to occur de novo in individuals with nonsyndromic intellectual disability (see for example at Rauch et al. 2012. PubMed ID: 23020937, described as chr12: g.111748354G>A at Table 4 and Supplementary Table S2 & S8; Kosmicki et al. 2017. PubMed ID: 28191890, Supplementary Table 2; Geisheker et al. 2017. PubMed ID: 28628100, Suppl. Table 4; Iwama et al. 2019. PubMed ID: 30842224). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 34758253, 23020937, 28191890, 30842224, 24866042, 29630738, 28628100, 29795476)
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. |
Comment:
This variant is interpreted as a Likely pathogenic for Epileptic encephalopathy, early infantile, 67, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate : PS4 downgraded in strength to Moderate (Variant absent from controls and recurrent in multiple unrelated patients PMID:28628100,23020937,29630738,29795476). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6-Strong : PM6 upgraded in strength to Strong (Assumed de novo in multiple unrelated patients PMID:28628100,23020937,29630738,29795476).
Comment:
The CUX2 c.1768G>A variant is predicted to result in the amino acid substitution p.Glu590Lys. This variant has been repeatedly reported to occur de novo in individuals with nonsyndromic intellectual disability (see for example at Rauch et al. 2012. PubMed ID: 23020937, described as chr12: g.111748354G>A at Table 4 and Supplementary Table S2 & S8; Kosmicki et al. 2017. PubMed ID: 28191890, Supplementary Table 2; Geisheker et al. 2017. PubMed ID: 28628100, Suppl. Table 4; Iwama et al. 2019. PubMed ID: 30842224). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 34758253, 23020937, 28191890, 30842224, 24866042, 29630738, 28628100, 29795476)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder. | Barington M | European journal of human genetics : EJHG | 2018 | PMID: 29795476 |
| The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. | Chatron N | Annals of neurology | 2018 | PMID: 29630738 |
| Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. | Geisheker MR | Nature neuroscience | 2017 | PMID: 28628100 |
| Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. | Rauch A | Lancet (London, England) | 2012 | PMID: 23020937 |
Text-mined citations for this variant ...
HelpRecord last updated Oct 08, 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.