Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25533962, 28053047, 28135719, 30564305, 33562844, 31785789, 33004838)
ClinVar Genomic variation as it relates to human health
NM_001347721.2(DYRK1A):c.664C>T (p.Arg222Ter)
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.
(7)
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
7
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.664C>T (p.Arg222Ter)
Variation ID: 423502 Accession: VCV000423502.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 37490201 (GRCh38) [ NCBI UCSC ] 21: 38862503 (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 27, 2017 Mar 23, 2024 Jul 7, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001347721.2:c.664C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001334650.1:p.Arg222Ter nonsense NM_001347722.2:c.664C>T NP_001334651.1:p.Arg222Ter nonsense NM_001347723.2:c.577C>T NP_001334652.1:p.Arg193Ter nonsense NM_001396.5:c.691C>T NP_001387.2:p.Arg231Ter nonsense NM_101395.2:c.691C>T NP_567824.1:p.Arg231Ter nonsense NM_130436.2:c.664C>T NP_569120.1:p.Arg222Ter nonsense NM_130438.2:c.691C>T NP_569122.1:p.Arg231Ter nonsense NC_000021.9:g.37490201C>T NC_000021.8:g.38862503C>T NG_009366.1:g.127645C>T - Protein change
- R231*, R193*, R222*
- Other names
- -
- Canonical SPDI
- NC_000021.9:37490200: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
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2022 | RCV000481862.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 8, 2015 | RCV000622466.2 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2023 | RCV000698811.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 18, 2016 | RCV001265464.1 |
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
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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Pathogenic
(Oct 19, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450331.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Oct 08, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741114.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Seizures (present) , Optic nerve hypoplasia (present) , Microcephaly (present) , Joint hypermobility (present) , Autistic behavior (present) , Telangiectasia … (more)
Global developmental delay (present) , Seizures (present) , Optic nerve hypoplasia (present) , Microcephaly (present) , Joint hypermobility (present) , Autistic behavior (present) , Telangiectasia of the skin (present) , Few cafe-au-lait spots (present) , Strabismus (present) , Achilles tendon contracture (present) , Toe walking (present) , Increased serum lactate (present) , Hyperalaninemia (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Encephalopathy (present) , Microcephaly (present) , Cerebral palsy (present) , Global developmental delay (present) , Intellectual disability (present) , Autistic disorder of childhood onset (present) … (more)
Encephalopathy (present) , Microcephaly (present) , Cerebral palsy (present) , Global developmental delay (present) , Intellectual disability (present) , Autistic disorder of childhood onset (present) , Seizures (present) , Scoliosis (present) , Hypothyroidism (present) , Brisk reflexes (present) , Hypertonia (present) , Emotional lability (present) , Petechiae (present) , Vitamin D deficiency (present) , Joint hypermobility (present) , Pectus excavatum (present) , Feeding difficulties (present) , Visual impairment (present) (less)
Sex: male
|
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Pathogenic
(Aug 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000573208.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25533962, 28053047, 28135719, 30564305, 33562844, 31785789, 33004838) (less)
|
|
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Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000827498.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg231*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg231*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYRK1A are known to be pathogenic (PMID: 25944381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a neurodevelopmental disorder and multiple congenital anomalies (PMID: 28053047). ClinVar contains an entry for this variant (Variation ID: 423502). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047944.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop-gained variant c.664C>T (p.Arg222Ter) in DYRK1A has been reported previously as a de novo variant in an individual (Fitzgerald et al., 2015). This variant … (more)
The stop-gained variant c.664C>T (p.Arg222Ter) in DYRK1A has been reported previously as a de novo variant in an individual (Fitzgerald et al., 2015). This variant has been reported to the ClinVar database as Pathogenic. The c.664C>T variant is reported with allele frequency 0.0004% in gnomAD exomes and novel in 1000 Genomes. The nucleotide change c.664C>T in DYRK1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic . (less)
Clinical Features:
Global developmental delay (present) , Hypotonia (present)
|
|
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Pathogenic
(Apr 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801500.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The DYRK1A c.691C>T (p.Arg231Ter) stop gained variant has been reported in a de novo heterozygous state in two individuals with the key features of DYRK1A-related … (more)
The DYRK1A c.691C>T (p.Arg231Ter) stop gained variant has been reported in a de novo heterozygous state in two individuals with the key features of DYRK1A-related intellectual disability syndrome, including intellectual disability, developmental delay, microcephaly, and characteristic dysmorphic facial features (Fitzgerald et al. 2015; Valencia et al. 2015; Evers et al. 2017). At least one of the two also showed cardiac defect, ophthalmological abnormality, poor weight gain, delayed speech development, and short stature. The p.Arg231Ter variant is not present in the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it is predicted to produce an absent or severely truncated protein product, including loss of more than half of the protein kinase domain. Based on the collective evidence, the c.691C>T p.Arg231Ter variant is classified as pathogenic for DYRK1A-related intellectual disability syndrome. (less)
|
|
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Pathogenic
(Nov 18, 2016)
|
no assertion criteria provided
Method: provider interpretation
|
Complex neurodevelopmental disorder
Affected status: yes
Allele origin:
de novo
|
GenomeConnect - Simons Searchlight
Accession: SCV001443599.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-18 and interpreted as Pathogenic. Variant was initially … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-18 and interpreted as Pathogenic. Variant was initially reported on 2016-10-20 by GTR ID of laboratory name 1238. The reporting laboratory might also submit to ClinVar. (less)
Clinical Features:
Autistic behavior (present) , Echogenic fetal bowel (present) , Premature birth (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , … (more)
Autistic behavior (present) , Echogenic fetal bowel (present) , Premature birth (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Abnormality of vision (present) , Myopia (disease) (present) , Nystagmus (present) , Strabismus (present) , Optic atrophy (present) , Clumsiness (present) , Generalized hypotonia (present) , Hypertonia (present) , Microcephaly (present) , Seizures (present) , Absence seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Asthma (present) , Bronchitis (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Allergic rhinitis (present) (less)
Age: 10-19 years
Sex: female
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg231*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYRK1A are known to be pathogenic (PMID: 25944381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a neurodevelopmental disorder and multiple congenital anomalies (PMID: 28053047). ClinVar contains an entry for this variant (Variation ID: 423502). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The stop-gained variant c.664C>T (p.Arg222Ter) in DYRK1A has been reported previously as a de novo variant in an individual (Fitzgerald et al., 2015). This variant has been reported to the ClinVar database as Pathogenic. The c.664C>T variant is reported with allele frequency 0.0004% in gnomAD exomes and novel in 1000 Genomes. The nucleotide change c.664C>T in DYRK1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic .
Comment:
The DYRK1A c.691C>T (p.Arg231Ter) stop gained variant has been reported in a de novo heterozygous state in two individuals with the key features of DYRK1A-related intellectual disability syndrome, including intellectual disability, developmental delay, microcephaly, and characteristic dysmorphic facial features (Fitzgerald et al. 2015; Valencia et al. 2015; Evers et al. 2017). At least one of the two also showed cardiac defect, ophthalmological abnormality, poor weight gain, delayed speech development, and short stature. The p.Arg231Ter variant is not present in the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it is predicted to produce an absent or severely truncated protein product, including loss of more than half of the protein kinase domain. Based on the collective evidence, the c.691C>T p.Arg231Ter variant is classified as pathogenic for DYRK1A-related intellectual disability syndrome.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-18 and interpreted as Pathogenic. Variant was initially reported on 2016-10-20 by GTR ID of laboratory name 1238. The reporting laboratory might also submit to ClinVar.
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:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25533962, 28053047, 28135719, 30564305, 33562844, 31785789, 33004838)
Comment:
This sequence change creates a premature translational stop signal (p.Arg231*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYRK1A are known to be pathogenic (PMID: 25944381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a neurodevelopmental disorder and multiple congenital anomalies (PMID: 28053047). ClinVar contains an entry for this variant (Variation ID: 423502). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The stop-gained variant c.664C>T (p.Arg222Ter) in DYRK1A has been reported previously as a de novo variant in an individual (Fitzgerald et al., 2015). This variant has been reported to the ClinVar database as Pathogenic. The c.664C>T variant is reported with allele frequency 0.0004% in gnomAD exomes and novel in 1000 Genomes. The nucleotide change c.664C>T in DYRK1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic .
Comment:
The DYRK1A c.691C>T (p.Arg231Ter) stop gained variant has been reported in a de novo heterozygous state in two individuals with the key features of DYRK1A-related intellectual disability syndrome, including intellectual disability, developmental delay, microcephaly, and characteristic dysmorphic facial features (Fitzgerald et al. 2015; Valencia et al. 2015; Evers et al. 2017). At least one of the two also showed cardiac defect, ophthalmological abnormality, poor weight gain, delayed speech development, and short stature. The p.Arg231Ter variant is not present in the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it is predicted to produce an absent or severely truncated protein product, including loss of more than half of the protein kinase domain. Based on the collective evidence, the c.691C>T p.Arg231Ter variant is classified as pathogenic for DYRK1A-related intellectual disability syndrome.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-11-18 and interpreted as Pathogenic. Variant was initially reported on 2016-10-20 by GTR ID of laboratory name 1238. The reporting laboratory might also submit to ClinVar.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders. | Evers JM | Human molecular genetics | 2017 | PMID: 28053047 |
| DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. | Ji J | European journal of human genetics : EJHG | 2015 | PMID: 25944381 |
Text-mined citations for rs780441716 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.