This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male with global delays, autism, microcephaly, dysmorphic features, ptosis
ClinVar Genomic variation as it relates to human health
NM_001347721.2(DYRK1A):c.586C>T (p.Arg196Ter)
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.
(14)
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
14
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.586C>T (p.Arg196Ter)
Variation ID: 162153 Accession: VCV000162153.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.13 21: 37486563 (GRCh38) [ NCBI UCSC ] 21: 38858865 (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 10, 2015 Aug 25, 2024 May 2, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001347721.2:c.586C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001334650.1:p.Arg196Ter nonsense NM_001347722.2:c.586C>T NP_001334651.1:p.Arg196Ter nonsense NM_001347723.2:c.499C>T NP_001334652.1:p.Arg167Ter nonsense NM_001396.4:c.613C>T NM_001396.5:c.613C>T NP_001387.2:p.Arg205Ter nonsense NM_101395.2:c.613C>T NP_567824.1:p.Arg205Ter nonsense NM_130436.2:c.586C>T NP_569120.1:p.Arg196Ter nonsense NM_130438.2:c.613C>T NP_569122.1:p.Arg205Ter nonsense NC_000021.9:g.37486563C>T NC_000021.8:g.38858865C>T NG_009366.1:g.124007C>T - Protein change
- R205*, R196*, R167*
- Other names
-
NM_001347721.2(DYRK1A):c.586C>T
p.Arg196Ter
- Canonical SPDI
- NC_000021.9:37486562:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Sep 9, 2014 | RCV000149559.4 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
May 2, 2023 | RCV000190478.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2014 | RCV000224593.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 6, 2023 | RCV000578685.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003637.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 21, 2020 | RCV001267263.5 |
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
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: SCV000206786.1 First in ClinVar: Sep 04, 2015 Last updated: Sep 04, 2015 |
Clinical Features:
Microcephaly (present) , Intrauterine growth retardation (present) , Brain abnormalities (present) , Global developmental delay (present) , Intellectual disability (present) , Severe speech delay (present) … (more)
Microcephaly (present) , Intrauterine growth retardation (present) , Brain abnormalities (present) , Global developmental delay (present) , Intellectual disability (present) , Severe speech delay (present) , Seizures (present) , Broad-based gait (present) , Short stature (present) , Minor skeletal anomalies (present) , Distinct facial gestal (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Asian/indian
Tissue: Blood
|
|
|
Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV000807303.2
First in ClinVar: Sep 04, 2015 Last updated: Dec 11, 2022 |
Comment:
This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male … (more)
This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male with global delays, autism, microcephaly, dysmorphic features, ptosis (less)
|
|
|
Pathogenic
(Mar 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000680693.3
First in ClinVar: Feb 13, 2018 Last updated: Mar 18, 2023 |
Comment:
Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); Nonsense variant predicted to result in protein truncation … (more)
Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); 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, 25641759, 26922654, 25944381, 25920557, 31263215, 32581362, 25167861, 28167836, 32838606, 33562844, 35873028, 35285131) (less)
|
|
|
Pathogenic
(Apr 20, 2023)
|
criteria provided, single submitter
Method: research
|
DYRK1A-related intellectual disability syndrome
Affected status: yes
Allele origin:
de novo
|
Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003919083.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
|
|
|
Pathogenic
(May 02, 2023)
|
criteria provided, single submitter
Method: curation
|
DYRK1A-related intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922184.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter … (more)
The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter variant in DYRK1A has been previously reported in the literature in 10 unrelated individuals with DYRK1A-related intellectual disability syndrome (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 32581362, PMID: 25920557). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 9 individuals with confirmed paternity and maternity (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 25920557, SCV002521469.1, SCV000196058.1). This variant has also been reported in ClinVar (Variation ID: 162153) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg205Ter variant may impact protein function (PMID 28167836, PMID: 31263215). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DYRK1A gene is an established disease mechanism in autosomal dominant DYRK1A-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DYRK1A-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS3_Moderate, PS4, PM2_Supporting (Richards 2015). (less)
|
|
|
Pathogenic
(Jan 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823367.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445444.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a … (more)
The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 205. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DYRK1A NM_001396 c.613C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported to have occurred de novo in multiple individuals with features consistent with a DYRK1A-related neurodevelopmental disorder including intellectual disability/developmental delay, seizures, microcephaly and dysmorphic facial features (Redin, 2014; Ruaud, 2015; Ji, 2015). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 25, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
Affected status: yes
Allele origin:
de novo
|
Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV000281731.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521469.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162153 / PMID: 25167861). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Attention deficit hyperactivity disorder (present) , Microcephaly (present) , Macrotia (present) , Clinodactyly of the 5th finger (present) , Hypoplasia of the … (more)
Seizure (present) , Attention deficit hyperactivity disorder (present) , Microcephaly (present) , Macrotia (present) , Clinodactyly of the 5th finger (present) , Hypoplasia of the corpus callosum (present) (less)
|
|
|
Pathogenic
(May 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
DYRK1A-related intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000955180.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg205*) 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.Arg205*) 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 disease (PMID: 25167861, 25641759, 25920557, 25944381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162153). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196654.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Sep 09, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability
Microcephaly Feeding difficulties Absent or delayed speech development Deeply set eye
Affected status: yes
Allele origin:
de novo
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV000196058.1
First in ClinVar: Jan 10, 2015 Last updated: Jan 10, 2015 |
Sex: male
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Microcephaly
Microphthalmia Global developmental delay Generalized-onset seizure
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162064.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: male
|
|
|
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: SCV001432338.1
First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020 |
|
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Comment:
Comment:
Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); 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, 25641759, 26922654, 25944381, 25920557, 31263215, 32581362, 25167861, 28167836, 32838606, 33562844, 35873028, 35285131)
Comment:
The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter variant in DYRK1A has been previously reported in the literature in 10 unrelated individuals with DYRK1A-related intellectual disability syndrome (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 32581362, PMID: 25920557). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 9 individuals with confirmed paternity and maternity (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 25920557, SCV002521469.1, SCV000196058.1). This variant has also been reported in ClinVar (Variation ID: 162153) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg205Ter variant may impact protein function (PMID 28167836, PMID: 31263215). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DYRK1A gene is an established disease mechanism in autosomal dominant DYRK1A-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DYRK1A-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS3_Moderate, PS4, PM2_Supporting (Richards 2015).
Comment:
The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 205. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DYRK1A NM_001396 c.613C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported to have occurred de novo in multiple individuals with features consistent with a DYRK1A-related neurodevelopmental disorder including intellectual disability/developmental delay, seizures, microcephaly and dysmorphic facial features (Redin, 2014; Ruaud, 2015; Ji, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162153 / PMID: 25167861). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change creates a premature translational stop signal (p.Arg205*) 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 disease (PMID: 25167861, 25641759, 25920557, 25944381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162153). 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:
This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male with global delays, autism, microcephaly, dysmorphic features, ptosis
Comment:
Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); 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, 25641759, 26922654, 25944381, 25920557, 31263215, 32581362, 25167861, 28167836, 32838606, 33562844, 35873028, 35285131)
Comment:
The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter variant in DYRK1A has been previously reported in the literature in 10 unrelated individuals with DYRK1A-related intellectual disability syndrome (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 32581362, PMID: 25920557). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 9 individuals with confirmed paternity and maternity (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 25920557, SCV002521469.1, SCV000196058.1). This variant has also been reported in ClinVar (Variation ID: 162153) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg205Ter variant may impact protein function (PMID 28167836, PMID: 31263215). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DYRK1A gene is an established disease mechanism in autosomal dominant DYRK1A-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DYRK1A-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS3_Moderate, PS4, PM2_Supporting (Richards 2015).
Comment:
The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 205. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DYRK1A NM_001396 c.613C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported to have occurred de novo in multiple individuals with features consistent with a DYRK1A-related neurodevelopmental disorder including intellectual disability/developmental delay, seizures, microcephaly and dysmorphic facial features (Redin, 2014; Ruaud, 2015; Ji, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162153 / PMID: 25167861). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change creates a premature translational stop signal (p.Arg205*) 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 disease (PMID: 25167861, 25641759, 25920557, 25944381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162153). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| 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 |
| Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A. | Bronicki LM | European journal of human genetics : EJHG | 2015 | PMID: 25920557 |
| DYRK1A mutations in two unrelated patients. | Ruaud L | European journal of medical genetics | 2015 | PMID: 25641759 |
| Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. | Redin C | Journal of medical genetics | 2014 | PMID: 25167861 |
Text-mined citations for rs724159949 ...
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Record last updated Oct 08, 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.