VCV000204005.12 - ClinVar

NM_001347721.2(DYRK1A):c.1372C>T (p.Arg458Ter)

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.1372C>T (p.Arg458Ter)

Variation ID: 204005 Accession: VCV000204005.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.13 21: 37505442 (GRCh38) [ NCBI UCSC ] 21: 38877745 (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	Sep 4, 2015	Feb 14, 2024	Jul 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001347721.2:c.1372C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001334650.1:p.Arg458Ter	nonsense
NM_001347722.2:c.1372C>T	NP_001334651.1:p.Arg458Ter	nonsense
NM_001347723.2:c.1285C>T	NP_001334652.1:p.Arg429Ter	nonsense
NM_001396.5:c.1399C>T	NP_001387.2:p.Arg467Ter	nonsense
NM_101395.2:c.1399C>T	NP_567824.1:p.Arg467Ter	nonsense
NM_130436.2:c.1372C>T	NP_569120.1:p.Arg458Ter	nonsense
NM_130438.2:c.1399C>T	NP_569122.1:p.Arg467Ter	nonsense
NC_000021.9:g.37505442C>T
NC_000021.8:g.38877745C>T
NG_009366.1:g.142887C>T

... more HGVS ... less HGVS

Protein change

R467*, R458*, R429*

Other names

Canonical SPDI

NC_000021.9:37505441: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: CA278526 dbSNP: rs797044520 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	977	1053

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.
DYRK1A-related intellectual disability syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 16, 2023	RCV000190479.10
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 3, 2022	RCV000522958.4
DYRK1A-related disorder	Pathogenic (1)	criteria provided, single submitter	-	RCV001731507.1

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.
Pathogenic (Sep 15, 2014)	criteria provided, single submitter (Submitter's publication) Method: clinical testing	Mental retardation, autosomal dominant 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	UCLA Clinical Genomics Center, UCLA Study: DYRK1A Haploinsufficiency Syndrome Accession: SCV000206787.1 First in ClinVar: Sep 04, 2015 Last updated: Sep 04, 2015	Publications: PubMed (1) PubMed: 25944381 Clinical Features: Brain abnormalities (present) , Global developmental delay (present) , Intellectual disability (present) , Severe speech delay (present) , Seizures (present) , Short stature (present) , … (more) Brain abnormalities (present) , Global developmental delay (present) , Intellectual disability (present) , Severe speech delay (present) , Seizures (present) , Short stature (present) , Minor skeletal anomalies (present) , Distinct facial gestal (present) (less) Age: 10-19 years Sex: male Ethnicity/Population group: European Tissue: Blood
Pathogenic (Oct 28, 2012)	criteria provided, single submitter (Yang et al. 2013) Method: clinical testing	Mental retardation, autosomal dominant 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Study: Adult_WES Accession: SCV000245476.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 26633545 Comment: This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 18-year-old male … (more) This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 18-year-old male with austistic spectrum, moderate intellectual disability, hypotonia, spasticity and ataxia, knee contractures, seizures, dysmorphisms, tall stature, hallux valgus, microcephaly, optic nerve pallor, orchiopexy/inguinal hernia repaired, dermoid or pilomatrixoma spontaneously resolved (less) Number of individuals with the variant: 1 Age: 10-19 years Sex: male Ethnicity/Population group: Causasians
Pathogenic (Aug 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DYRK1A-related intellectual disability syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genomic Medicine Lab, University of California San Francisco Study: CSER-P3EGS Accession: SCV001573040.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021	Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DYRK1A-related disorder Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Study: CSER-NYCKidSeq Accession: SCV001984778.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: This nonsense variant occurs in exon 9 of 11 and is predicted to result in loss of normal protein function through either protein truncation or … (more) This nonsense variant occurs in exon 9 of 11 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously identified in multiple individuals with developmental regression, microcephaly, intellectual disability, global developmental delay, severe speech delay, seizures, feeding difficulties, and autism spectrum disorder (PMID: 26677511, 30831192, 25944381). Loss-of-function variation is an established mechanism of disease for DYRK1A-related disorders (PMID: 26677511). The c.1399C>T (p.Arg467Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1399C>T (p.Arg467Ter) variant is classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DYRK1A-related intellectual disability syndrome Affected status: unknown Allele origin: de novo	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV002576348.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022
Pathogenic (Oct 03, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618033.5 First in ClinVar: Dec 19, 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 disease; Not … (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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34345024, 26633545, 31263215, 25944381, 31216405, 30831192) (less)
Pathogenic (Jul 16, 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: SCV003444390.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 25944381 Comment: This sequence change creates a premature translational stop signal (p.Arg467) 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.Arg467) 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 DYRK1A-related conditions (PMID: 25944381). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 204005). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	DYRK1A-related intellectual disability syndrome Affected status: yes Allele origin: unknown	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001432351.1 First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020

Comment:

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 18-year-old male with austistic spectrum, moderate intellectual disability, hypotonia, spasticity and ataxia, knee contractures, seizures, dysmorphisms, tall stature, hallux valgus, microcephaly, optic nerve pallor, orchiopexy/inguinal hernia repaired, dermoid or pilomatrixoma spontaneously resolved

Comment:

This nonsense variant occurs in exon 9 of 11 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously identified in multiple individuals with developmental regression, microcephaly, intellectual disability, global developmental delay, severe speech delay, seizures, feeding difficulties, and autism spectrum disorder (PMID: 26677511, 30831192, 25944381). Loss-of-function variation is an established mechanism of disease for DYRK1A-related disorders (PMID: 26677511). The c.1399C>T (p.Arg467Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1399C>T (p.Arg467Ter) variant is classified as Pathogenic.

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34345024, 26633545, 31263215, 25944381, 31216405, 30831192)

Comment:

This sequence change creates a premature translational stop signal (p.Arg467*) 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 DYRK1A-related conditions (PMID: 25944381). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 204005). For these reasons, this variant has been classified as Pathogenic.

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
Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome.	Arranz J	Neurobiology of disease	2019	PMID: 30831192
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
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 rs797044520 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001347721.2(DYRK1A):c.1372C>T (p.Arg458Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs797044520 ...