[ACMG/AMP: PS2, PM2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
ClinVar Genomic variation as it relates to human health
NM_001347721.2(DYRK1A):c.638-9_638-5del
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_001347721.2(DYRK1A):c.638-9_638-5del
Variation ID: 487250 Accession: VCV000487250.18
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 21q22.13 21: 37490164-37490168 (GRCh38) [ NCBI UCSC ] 21: 38862466-38862470 (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 Jan 6, 2018 Nov 17, 2024 Oct 14, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001347721.2:c.638-9_638-5del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001347721.1:c.638-9_638-5delCTCTT NM_001347722.2:c.638-9_638-5del intron variant NM_001347723.2:c.551-9_551-5del intron variant NM_001396.3:c.665-9_665-5delCTCTT NM_001396.5:c.665-9_665-5del intron variant NM_101395.2:c.665-9_665-5del intron variant NM_101395.2:c.665-9_665-5delCTCTT NM_130436.2:c.638-9_638-5del intron variant NM_130436.2:c.638-9_638-5delCTCTT NM_130438.2:c.665-9_665-5del intron variant NC_000021.9:g.37490166_37490170del NC_000021.8:g.38862468_38862472del NG_009366.1:g.127610_127614del - Protein change
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- Other names
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- Canonical SPDI
- NC_000021.9:37490163:TTCTCTT:TT
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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. |
|||
| DYRK1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
984 | 1060 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2024 | RCV000576181.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2022 | RCV001268095.4 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2022 | RCV003156105.2 |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 10, 2020 | RCV001260680.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: yes
Allele origin:
germline
|
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423647.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
Comment:
[ACMG/AMP: PS2, PM2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is … (more)
[ACMG/AMP: PS2, PM2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
|
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446747.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Facial hypotonia (present) , Global developmental delay (present) , Gait ataxia (present) , Short stature (present)
Sex: male
|
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Likely pathogenic
(Sep 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
Affected status: yes
Allele origin:
de novo
|
Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437772.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Method: targeted next-gen sequencing
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|
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Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002765792.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25707398, 28135719, 32371413, 28252636, 31526516, 33562844, 34345024) (less)
|
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Likely pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
de novo
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845251.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Absent speech (present) , Failure to thrive (present) , Global developmental delay (present) , Insomnia (present) , Large for gestational age (present) , Low-set ears … (more)
Absent speech (present) , Failure to thrive (present) , Global developmental delay (present) , Insomnia (present) , Large for gestational age (present) , Low-set ears (present) , Microcephaly (present) , Posteriorly rotated ears (present) , Preauricular pit (present) , Short stature (present) , Single transverse palmar crease (present) (less)
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Pathogenic
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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DYRK1A-related intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000677027.5
First in ClinVar: Jan 06, 2018 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 487250). This variant has been observed in individual(s) with DYRK1A-related disease (PMID: 25707398; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the DYRK1A gene. It does not directly change the encoded amino acid sequence of the DYRK1A protein. It affects a nucleotide within the consensus splice site. (less)
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Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003922009.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
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 DYRK1A-related intellectual disability syndrome, MONDO: 0013578. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in the ClinVar database, and twice in the literature as de novo in individuals with intellectual disability and other features (PMID: 25707398, 32371413). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005397118.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Clinical Features:
Microcephaly (present) , Epileptic encephalopathy (present) , Spasticity (present) , Autism (present) , Severe global developmental delay (present) , Generalized-onset seizure (present)
Sex: female
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: yes
Allele origin:
unknown
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Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432317.1
First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020 |
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25707398, 28135719, 32371413, 28252636, 31526516, 33562844, 34345024)
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 487250). This variant has been observed in individual(s) with DYRK1A-related disease (PMID: 25707398; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the DYRK1A gene. It does not directly change the encoded amino acid sequence of the DYRK1A protein. It affects a nucleotide within the consensus splice site.
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 of disease in this gene and is associated with DYRK1A-related intellectual disability syndrome, MONDO: 0013578. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in the ClinVar database, and twice in the literature as de novo in individuals with intellectual disability and other features (PMID: 25707398, 32371413). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
[ACMG/AMP: PS2, PM2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25707398, 28135719, 32371413, 28252636, 31526516, 33562844, 34345024)
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 487250). This variant has been observed in individual(s) with DYRK1A-related disease (PMID: 25707398; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the DYRK1A gene. It does not directly change the encoded amino acid sequence of the DYRK1A protein. It affects a nucleotide within the consensus splice site.
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 of disease in this gene and is associated with DYRK1A-related intellectual disability syndrome, MONDO: 0013578. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in the ClinVar database, and twice in the literature as de novo in individuals with intellectual disability and other features (PMID: 25707398, 32371413). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience. | Miller CR | Cold Spring Harbor molecular case studies | 2020 | PMID: 32371413 |
| Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. | van Bon BW | Molecular psychiatry | 2016 | PMID: 25707398 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for this variant ...
HelpRecord last updated Nov 19, 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.