VCV000373087.42 - ClinVar

NM_001347721.2(DYRK1A):c.322C>T (p.Arg108Ter)

Germline

Classification

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.

(8)

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

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.322C>T (p.Arg108Ter)

Variation ID: 373087 Accession: VCV000373087.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.13 21: 37480659 (GRCh38) [ NCBI UCSC ] 21: 38852961 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 9, 2017	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001347721.2:c.322C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001334650.1:p.Arg108Ter	nonsense
NM_001347722.2:c.322C>T	NP_001334651.1:p.Arg108Ter	nonsense
NM_001347723.2:c.235C>T	NP_001334652.1:p.Arg79Ter	nonsense
NM_001396.5:c.349C>T	NP_001387.2:p.Arg117Ter	nonsense
NM_101395.2:c.349C>T	NP_567824.1:p.Arg117Ter	nonsense
NM_130436.2:c.322C>T	NP_569120.1:p.Arg108Ter	nonsense
NM_130438.2:c.349C>T	NP_569122.1:p.Arg117Ter	nonsense
NC_000021.9:g.37480659C>T
NC_000021.8:g.38852961C>T
NG_009366.1:g.118103C>T

... more HGVS ... less HGVS

Protein change

R117*, R108*, R79*

Other names

Canonical SPDI

NC_000021.9:37480658:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA16043144 dbSNP: rs1057518204 VarSome

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
Gene	OMIM	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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 16, 2021	RCV000413934.32
DYRK1A-related intellectual disability syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000499667.21
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2015	RCV000623331.10
Complex neurodevelopmental disorder	Pathogenic (1)	no assertion criteria provided	Aug 25, 2017	RCV001265465.9

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.
Pathogenic (Oct 20, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mental retardation, autosomal dominant 7 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594471.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (Mar 27, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000740863.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Short stature (present) , Delayed skeletal maturation (present) , Microcephaly (present) , Seizures (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) … (more) Short stature (present) , Delayed skeletal maturation (present) , Microcephaly (present) , Seizures (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) , Behavioral abnormality (present) , Anxiety (present) , Anemia (present) , Vesicoureteral reflux (present) , Coxa valga (present) , Lower limb hyperreflexia (present) , Chronic constipation (present) , Strabismus (present) , Epicanthus (present) , Malar flattening (present) , Long nose (present) , Asymmetric, linear skin defects (present) , Pectus excavatum (present) , Decreased fetal movement (present) (less) Sex: female
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491650.4 First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023	Comment: Reported previously in an individual with seizures and intellectual disability; however additional details were not provided (Helbig et al., 2016); Nonsense variant predicted to result … (more) Reported previously in an individual with seizures and intellectual disability; however additional details were not provided (Helbig et al., 2016); 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28191889, 33562844, 33004838, 26795593) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DYRK1A-related intellectual disability syndrome Affected status: yes Allele origin: de novo	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559158.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	DYRK1A-related intellectual disability syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002181783.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 25944381‚ 26795593‚ 28191889‚ 33004838 Comment: This sequence change creates a premature translational stop signal (p.Arg117) 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.Arg117) 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 clinical features of DYRK1A-related conditions (PMID: 26795593, 28191889, 33004838). ClinVar contains an entry for this variant (Variation ID: 373087). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DYRK1A-related intellectual disability syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Laboratory Cellgenetics, GMDL Cellgenetics Accession: SCV004697449.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024	Sex: male
Pathogenic (Nov 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246784.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Aug 25, 2017)	no assertion criteria provided Method: provider interpretation	Complex neurodevelopmental disorder Affected status: yes Allele origin: de novo	GenomeConnect - Simons Searchlight Accession: SCV001443600.1 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 2017-08-25 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 2017-08-25 and interpreted as Pathogenic. Variant was initially reported on 2017-07-05 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. (less) Clinical Features: Autistic behavior (present) , Forceps delivery (present) , Ventouse delivery (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal … (more) Autistic behavior (present) , Forceps delivery (present) , Ventouse delivery (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Strabismus (present) , Microcephaly (present) , Cerebral palsy (present) , Seizure precipitated by febrile infection (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Palpitations (present) , Failure to thrive (present) , Abnormality of the skeletal system (present) , Scoliosis (present) , Abnormality of the skin (present) , Acne (present) , Abnormality of the cardiovascular system (present) (less) Age: 10-19 years Sex: male

Comment:

Reported previously in an individual with seizures and intellectual disability; however additional details were not provided (Helbig et al., 2016); 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28191889, 33562844, 33004838, 26795593)

Comment:

This sequence change creates a premature translational stop signal (p.Arg117*) 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 clinical features of DYRK1A-related conditions (PMID: 26795593, 28191889, 33004838). ClinVar contains an entry for this variant (Variation ID: 373087). For these reasons, this variant has been classified as Pathogenic.

Comment:

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-08-25 and interpreted as Pathogenic. Variant was initially reported on 2017-07-05 by GTR ID of laboratory name 26957. 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.	Wang T	Nature communications	2020	PMID: 33004838
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.	Stessman HA	Nature genetics	2017	PMID: 28191889
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.	Helbig KL	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26795593
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 rs1057518204 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001347721.2(DYRK1A):c.322C>T (p.Arg108Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057518204 ...