ClinVar Genomic variation as it relates to human health
NM_001356.5(DDX3X):c.977G>A (p.Arg326His)
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_001356.5(DDX3X):c.977G>A (p.Arg326His)
Variation ID: 208547 Accession: VCV000208547.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 41344351 (GRCh38) [ NCBI UCSC ] X: 41203604 (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 Jul 6, 2017 Oct 20, 2024 Jan 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001356.5:c.977G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001347.3:p.Arg326His missense NM_001193416.2:c.977G>A NM_001193416.3:c.977G>A NP_001180345.1:p.Arg326His missense NM_001193417.3:c.929G>A NP_001180346.1:p.Arg310His missense NM_001363819.1:c.419G>A NP_001350748.1:p.Arg140His missense NR_126093.1:n.1922G>A non-coding transcript variant NC_000023.11:g.41344351G>A NC_000023.10:g.41203604G>A NG_012830.2:g.15954G>A O00571:p.Arg326His - Protein change
- R326H, R310H, R140H
- Other names
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- Canonical SPDI
- NC_000023.11:41344350:G:A
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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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- Links
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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DDX3X | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
763 | 920 |
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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000190552.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2019 | RCV000521776.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2016 | RCV000623237.3 | |
not provided (1) |
no classification provided
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- | RCV003313052.3 |
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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Pathogenic
(Oct 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741811.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Muscular hypotonia (present) , Failure to thrive (present) , Short stature (present) , Pyloric stenosis (present) , Microcephaly (present) , Brachycephaly (present) , Low-set ears … (more)
Muscular hypotonia (present) , Failure to thrive (present) , Short stature (present) , Pyloric stenosis (present) , Microcephaly (present) , Brachycephaly (present) , Low-set ears (present) , Strabismus (present) , Epicanthus (present) , Upslanted palpebral fissure (present) , Hypertelorism (present) , High palate (present) , Wide intermamillary distance (present) , Toe syndactyly (present) , Nevus (present) , Breathing dysregulation (present) , Neurodevelopmental delay (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
Observation 2:
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jul 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked 102
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149749.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked 102
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058936.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32135084, , PS3_S). A different missense … (more)
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32135084, , PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521573, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.614, 3CNET: 0.991, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26235985, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal nasal bridge morphology (present) , Corpus callosum, agenesis of (present) , Cerebellar vermis hypoplasia (present) , Gastroesophageal reflux (present) , Hypoglycemia (present) , Inguinal … (more)
Abnormal nasal bridge morphology (present) , Corpus callosum, agenesis of (present) , Cerebellar vermis hypoplasia (present) , Gastroesophageal reflux (present) , Hypoglycemia (present) , Inguinal hernia (present) , Intellectual disability, moderate (present) , Ventriculomegaly (present) , Low-set, posteriorly rotated ears (present) , Micrognathia (present) , Single transverse palmar crease (present) , Single umbilical artery (present) (less)
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Pathogenic
(Jun 01, 2018)
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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: SCV001250516.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 23, 2019)
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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: SCV000618041.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135719, 26235985, 29346770, 30125339, 32135084) (less)
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Pathogenic
(Aug 06, 2015)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000245433.3
First in ClinVar: Sep 06, 2015 Last updated: May 09, 2020 |
Comment on evidence:
In a 13-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.977G-A … (more)
In a 13-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.977G-A transition (c.977G-A, NM_001356.4) in the DDX3X gene, resulting in an arg326-to-his (R326H) substitution in the helicase ATP-binding domain. The mutation, which was found by whole-exome sequencing of several large cohorts of patients with intellectual disability, was not found in the ExAC or Exome Variant Server databases. In vitro cellular functional expression studies and in vivo studies in zebrafish indicated that the R326H mutation caused a loss of protein function, consistent with haploinsufficiency. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Syndromic X-linked intellectual disability Claes-Jensen type
Affected status: yes
Allele origin:
de novo
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GenomeConnect - Brain Gene Registry
Accession: SCV004012802.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Comment:
Variant interpreted as Pathogenic and reported on 10-20-2017 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more)
Variant interpreted as Pathogenic and reported on 10-20-2017 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Autistic behavior (present) , Intellectual disability (present) , Dystonic disorder (present) , Brain imaging abnormality (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-10-20
Testing laboratory interpretation: Pathogenic
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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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Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. | Lennox AL | Neuron | 2020 | PMID: 32135084 |
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. | Snijders Blok L | American journal of human genetics | 2015 | PMID: 26235985 |
Birth of the D-E-A-D box. | Linder P | Nature | 1989 | PMID: 2563148 |
Text-mined citations for rs797045025 ...
HelpRecord last updated Oct 20, 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.