ClinVar Genomic variation as it relates to human health
NM_020699.4(GATAD2B):c.1241G>A (p.Arg414Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020699.4(GATAD2B):c.1241G>A (p.Arg414Gln)
Variation ID: 381463 Accession: VCV000381463.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.3 1: 153813428 (GRCh38) [ NCBI UCSC ] 1: 153785904 (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 Mar 8, 2017 May 12, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020699.4:c.1241G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065750.1:p.Arg414Gln missense NC_000001.11:g.153813428C>T NC_000001.10:g.153785904C>T NG_050988.1:g.114548G>A - Protein change
- R414Q
- Other names
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- Canonical SPDI
- NC_000001.11:153813427: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GATAD2B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
518 | 538 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000433516.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000986415.4 |
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
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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
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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
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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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Likely pathogenic
(Oct 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000520738.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The R414Q variant in the GATAD2B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The R414Q variant in the GATAD2B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R414Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R414Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that this sequence change might create a cryptic acceptor site in exon 8 which may supplant the natural acceptor site. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Based on the knowledge that the R414Q variant is likely de novo, we now consider it to be a strong candidate for a pathogenic variant (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135414.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004050291.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Likely pathogenic
(Aug 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004190171.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The c.1241G>A variant is a heterozygous single base pair substitution at nucleotide 1241 in exon 8 of 11 of the GATAD2B gene, resulting in a … (more)
The c.1241G>A variant is a heterozygous single base pair substitution at nucleotide 1241 in exon 8 of 11 of the GATAD2B gene, resulting in a substitution of a highly conserved arginine at amino acid position 414 to a glutamine (p.Arg414Gln). This variant is absent from the gnomAD database, indicating it is not a common benign occurrence in the populations represented in these databases. In silico predictors are inconsistent in predicting an effect on the structure and/or function of the protein (benign by PolyPhen2, tolerated by SIFT, disease causing by MutationTaster). The GATAD2B gene encodes GATA zinc finger domain-containing protein 2B, a subunit of the NuRD complex. The NuRD complex is an important regulator of gene expression with both histone deacetylase and chromatin remodeling activity. The arginine at position 414 falls in the CR2 conserved region, which contains a GATA-type zinc finger motif (PMID: 11756549) and is known to interact with other NuRD proteins. The p.Arg414Gln variant has been previously reported as de novo in two unrelated individuals with intellectual disability associated with expressive and receptive language issues (PMID: 31949314). Immunoprecipitation assays utilizing in vitro transcription-translation products revealed that the p.Arg414Gln variant causes a mild reduction in the interactions with CHD paralogues, disrupting assembly of NuRD complex proteins (PMID: 31949314). (less)
Clinical Features:
Delayed speech and language development (present) , Motor delay (present) , Relative macrocephaly (present) , Atrial septal defect (present) , Autism (present) , Abnormal facial … (more)
Delayed speech and language development (present) , Motor delay (present) , Relative macrocephaly (present) , Atrial septal defect (present) , Autism (present) , Abnormal facial shape (present) (less)
Family history: no
Age: 20-29 years
Sex: female
Ethnicity/Population group: Hispanic Americans
Geographic origin: Mexico
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Likely pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004704292.3
First in ClinVar: Mar 10, 2024 Last updated: May 12, 2024 |
Comment:
GATAD2B: PM2, PM6, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Oct 22, 2020)
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no assertion criteria provided
Method: literature only
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GAND SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001439212.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Comment on evidence:
In 2 unrelated patients (GAND28 and GAND49) with GAND syndrome (GAND; 615074), Shieh et al. (2020) identified a de novo heterozygous c.1241G-A transition (c.1241G-A, NM_020699.3) … (more)
In 2 unrelated patients (GAND28 and GAND49) with GAND syndrome (GAND; 615074), Shieh et al. (2020) identified a de novo heterozygous c.1241G-A transition (c.1241G-A, NM_020699.3) in exon 8 of the GATAD2B gene, resulting in an arg414-to-gln (R414Q) substitution at a conserved residue in the CR2 domain. The mutations were found by exome sequencing. In vitro immunoprecipitation studies showed that the R414Q mutation caused a mild reduction in the interaction of GATAD2B with CHD paralogs (see, e.g., CHD4; 603277) compared to wildtype. These findings were consistent with a partial loss-of-function effect. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder. | Shieh C | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31949314 |
Identification and functional characterization of the p66/p68 components of the MeCP1 complex. | Feng Q | Molecular and cellular biology | 2002 | PMID: 11756549 |
Text-mined citations for rs1057521041 ...
HelpRecord last updated May 12, 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.