ClinVar Genomic variation as it relates to human health
NM_001260.3(CDK8):c.185C>T (p.Ser62Leu)
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
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NM_001260.3(CDK8):c.185C>T (p.Ser62Leu)
Variation ID: 805981 Accession: VCV000805981.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.13 13: 26337623 (GRCh38) [ NCBI UCSC ] 13: 26911760 (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 Feb 3, 2020 Apr 15, 2024 Jun 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001260.3:c.185C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001251.1:p.Ser62Leu missense NM_001318368.2:c.185C>T NP_001305297.1:p.Ser62Leu missense NM_001346501.2:c.-277C>T 5 prime UTR NC_000013.11:g.26337623C>T NC_000013.10:g.26911760C>T - Protein change
- S62L
- Other names
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- Canonical SPDI
- NC_000013.11:26337622:C:T
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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CDK8 | - | - |
GRCh38 GRCh37 |
53 | 96 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, single submitter
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Mar 26, 2020 | RCV000993854.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2023 | RCV003994184.1 |
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
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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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Pathogenic
(Mar 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder with hypotonia and behavioral abnormalities
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430065.1
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Clinical Features:
Visual impairment (present) , Generalized hypotonia (present) , Colpocephaly (present) , Intellectual disability (present) , Cryptorchidism (present) , Hypoplasia of the pons (present)
Sex: male
Tissue: blood
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Pathogenic
(Jun 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Complex neurodevelopmental disorder with or without congenital anomalies
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812457.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in CDK8 is predicted to replace serine with leucine at codon 62, p.(Ser62Leu). The serine residue is highly conserved (97/97 vertebrates, UCSC), … (more)
This sequence change in CDK8 is predicted to replace serine with leucine at codon 62, p.(Ser62Leu). The serine residue is highly conserved (97/97 vertebrates, UCSC), and is located in the protein kinase domain. There is a large physicochemical difference between serine and leucine. CDK8, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1 missense constraint). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in four individuals, as a de novo occurrence with unconfirmed parental relationships in five individuals, and expected de novo with unknown inheritance in two individuals, all with a syndromic neurodevelopmental disorder (PMID: 30905399, 33958710; DECIPHER patient: 293709, 409614; ClinVar: SCV001430065.1, SCV001439334.1, SCV002075047.1). Phosphorylation assays in a mammalian cell line showed reduced STAT1 phosphorylation indicating that this variant impacts protein function (PMID: 30905399). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.644). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_VeryStrong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2, PP3. (less)
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Pathogenic
(Jul 29, 2020)
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no assertion criteria provided
Method: clinical testing
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Intellectual developmental disorder with hypotonia and behavioral abnormalities
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001439334.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Sep 11, 2023)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH HYPOTONIA AND BEHAVIORAL ABNORMALITIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001147012.2
First in ClinVar: Feb 03, 2020 Last updated: Sep 14, 2023 |
Comment on evidence:
In 5 unrelated patients (patients 4 though 8) with intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA; 618748), Calpena et al. (2019) identified a … (more)
In 5 unrelated patients (patients 4 though 8) with intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA; 618748), Calpena et al. (2019) identified a de novo heterozygous c.185C-T transition (c.185C-T, NM_001260.2) in exon 7 of the CDK8 gene, resulting in a ser62-to-leu (S62L) substitution at a highly conserved residue in the alpha-C-helix of the kinase domain. The mutation, which was found by whole-exome sequencing through different laboratories, was not found in the gnomAD database. Paternal DNA from 2 patients was unavailable to confirm de novo occurrence. In vitro functional expression studies in transfected human colorectal cancer cells (SW620) showed that the mutation strongly attenuated CDK8 kinase activity compared to controls. The authors postulated a dominant-negative effect; however, there was no reduction in CDK8 phosphorylation activity when S62L was mixed with wildtype CDK8. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Intellectual developmental disorder with hypotonia and behavioral abnormalities
Affected status: unknown
Allele origin:
de novo
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GenomeConnect, ClinGen
Accession: SCV002075047.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 03-18-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 03-18-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Generalized hypotonia (present) , Heterotaxy (present) , Delayed gross motor development (present) , Mitral atresia disorder (present) , Double outlet right ventricle (present) , Hypoplastic … (more)
Generalized hypotonia (present) , Heterotaxy (present) , Delayed gross motor development (present) , Mitral atresia disorder (present) , Double outlet right ventricle (present) , Hypoplastic left heart syndrome (present) , Congenital malformation of the great arteries (present) , Right isomerism (present) , Muscle fibrillation (present) , Gastrostomy tube feeding in infancy (present) , Hypoxemia (present) , Hematemesis (present) , Cardiomegaly (present) , Torticollis (present) , Plagiocephaly (present) , Bilateral cryptorchidism (present) , Abnormal penis morphology (present) , Small scrotum (present) , High palate (present) , Gestational diabetes (present) , Preeclampsia (present) , Persistent left superior vena cava (present) , Triatrial heart (present) , Bilobed right lung (present) , Retractile testis (present) , Keratosis pilaris (present) , Short stature (present) , Cafe-au-lait spot (present) , Bilateral ptosis (present) , Low-set ears (present) , Thickened nuchal skin fold (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2021-03-18
Testing laboratory interpretation: Pathogenic
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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 |
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Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies. | Miyamoto S | Journal of human genetics | 2021 | PMID: 33958710 |
De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. | Calpena E | American journal of human genetics | 2019 | PMID: 30905399 |
Text-mined citations for rs1565977796 ...
HelpRecord last updated Jun 23, 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.