ClinVar Genomic variation as it relates to human health
NM_003718.5(CDK13):c.484dup (p.Ala162fs)
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.
Pathogenic(4); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003718.5(CDK13):c.484dup (p.Ala162fs)
Variation ID: 504021 Accession: VCV000504021.18
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 7p14.1 7: 39951117-39951118 (GRCh38) [ NCBI UCSC ] 7: 39990716-39990717 (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 Apr 2, 2018 Feb 14, 2024 Aug 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003718.5:c.484dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003709.3:p.Ala162fs frameshift NM_003718.4:c.484dupG NM_031267.3:c.484dup NP_112557.2:p.Ala162fs frameshift NC_000007.14:g.39951125dup NC_000007.13:g.39990724dup NG_052965.1:g.5766dup - Protein change
- A162fs
- Other names
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- Canonical SPDI
- NC_000007.14:39951117:GGGGGGGG:GGGGGGGGG
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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.
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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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CDK13 | Some evidence for dosage pathogenicity | Not yet evaluated |
GRCh38 GRCh37 |
669 | 791 | |
LOC129998292 | - | - | - | GRCh38 | - | 81 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 29, 2023 | RCV000598864.8 | |
Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000786912.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000710325.5
First in ClinVar: Apr 02, 2018 Last updated: Sep 14, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 30525188, 29393965, 33879837, 31238879) (less)
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Uncertain significance
(Aug 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369345.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more)
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. (less)
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Pathogenic
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV002577731.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PVS1;PS4;PM2_supporting;PM6
Clinical Features:
Decreased circulating vitamin D concentration (present) , Inflammatory abnormality of the skin (present) , Astigmatism (present) , Abnormal facial shape (present) , Joint laxity (present) … (more)
Decreased circulating vitamin D concentration (present) , Inflammatory abnormality of the skin (present) , Astigmatism (present) , Abnormal facial shape (present) , Joint laxity (present) , Developmental dysplasia of the hip (present) , Strabismus (present) , Anemia (present) , Motor delay (present) , Genu valgum (present) , Hypotonia (present) , Delayed eruption of teeth (present) , Atypical behavior (present) (less)
Sex: female
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Uncertain significance
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769283.1
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 VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both dominant negative and haploinsufficiency have been suggested, although not proven with functional studies (PMID: 29393965, PMID: 30904094). (I) 0107 - This gene is associated with autosomal 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) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). However, this variant does not pass gnomAD data quality filters. (I) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Other NMD-predicted variants have been reported as pathogenic in ClinVar, and also in individuals with neurodevelopmental disorders in the literature (PMID: 29393965, 31238879). (SP) 0801 - This variant has previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in 3 unrelated patients with developmental delay, 2 of which were shown to be de novo (PMID: 29393965). This variant has also been reported in ClinVar both as pathogenic and as a VUS. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014724.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The CDK13 c.484dup (p.Ala162GlyfsTer108) variant is a duplication of a nucleotide at position c.484, causing a shift in the protein reading frame that is predicted … (more)
The CDK13 c.484dup (p.Ala162GlyfsTer108) variant is a duplication of a nucleotide at position c.484, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in at least four individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder; in three of these cases, the variant was confirmed to have a de novo occurrence (PMID: 29393965; PMID: 30525188). The p.Ala162GlyfsTer108 variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000026 in the Total population (version 3.1.2), however, these variants failed allele-specific VQSR filter, so this frequency data may be unreliable. This variant was identified in a de novo state. Based on the available evidence, the c.484dup (p.Ala162GlyfsTer108) variant is classified as pathogenic for congenital heart defects, dysmorphic facial features, and intellectual developmental disorder. (less)
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004032315.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PVS1,PS2_VSTR,PS4_MOD,PM2_SUP
Clinical Features:
Vertebral fusion (present) , Tetraparesis (present) , Cystocele (present) , Myelocystocele (present) , Short stature (present) , Urinary incontinence (present) , Specific learning disability (present) … (more)
Vertebral fusion (present) , Tetraparesis (present) , Cystocele (present) , Myelocystocele (present) , Short stature (present) , Urinary incontinence (present) , Specific learning disability (present) , Brachydactyly (present) , Nystagmus (present) , Dysphagia (present) , Cerebellar ataxia (present) , Left ventricular hypertrophy (present) , Distal sensory impairment of all modalities (present) , Clinodactyly (present) (less)
Sex: female
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Likely pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041411.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jul 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004311164.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 504021). 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: 504021). This premature translational stop signal has been observed in individual(s) with syndromic intellectual disability (PMID: 29393965). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala162Glyfs*108) in the CDK13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDK13 are known to be pathogenic (PMID: 27479907, 29021403, 29393965). (less)
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Pathogenic
(Dec 12, 2018)
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no assertion criteria provided
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000925813.1
First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019 |
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Pathogenic
(Aug 08, 2022)
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no assertion criteria provided
Method: clinical testing
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Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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MedGen Diagnostic Laboratory, MedGen Medical Centre
Accession: SCV002558802.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
Comment:
The variant is de novo. In patient we observed: short stature, dysmorphic features, intellectual disability. In summary, this variant meets criteria to be classified as … (more)
The variant is de novo. In patient we observed: short stature, dysmorphic features, intellectual disability. In summary, this variant meets criteria to be classified as pathogenic. (less)
Clinical Features:
Short stature (present) , Intellectual disability (present)
Age: 10-19 years
Sex: female
Geographic origin: Poland
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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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Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders. | Trinh J | Journal of neurodevelopmental disorders | 2019 | PMID: 31238879 |
CDK13-related disorder. | Hamilton MJ | Advances in genetics | 2019 | PMID: 30904094 |
Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. | Snoeijen-Schouwenaars FM | Epilepsia | 2019 | PMID: 30525188 |
De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review. | van den Akker WMR | Clinical genetics | 2018 | PMID: 29393965 |
Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. | Hamilton MJ | Journal of medical genetics | 2018 | PMID: 29021403 |
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. | Sifrim A | Nature genetics | 2016 | PMID: 27479907 |
Text-mined citations for rs1405252481 ...
HelpRecord last updated Feb 20, 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.