ClinVar Genomic variation as it relates to human health
NM_001356.5(DDX3X):c.874C>T (p.Arg292Ter)
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.874C>T (p.Arg292Ter)
Variation ID: 452201 Accession: VCV000452201.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 41344248 (GRCh38) [ NCBI UCSC ] X: 41203501 (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 Dec 19, 2017 May 1, 2024 Jul 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001356.5:c.874C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001347.3:p.Arg292Ter nonsense NM_001193416.3:c.874C>T NP_001180345.1:p.Arg292Ter nonsense NM_001193417.3:c.826C>T NP_001180346.1:p.Arg276Ter nonsense NM_001363819.1:c.316C>T NP_001350748.1:p.Arg106Ter nonsense NR_126093.1:n.1819C>T non-coding transcript variant NC_000023.11:g.41344248C>T NC_000023.10:g.41203501C>T NG_012830.2:g.15851C>T - Protein change
- R292*, R276*, R106*
- Other names
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- Canonical SPDI
- NC_000023.11:41344247: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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DDX3X | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
723 | 878 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000519583.21 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 14, 2020 | RCV001174975.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2017 | RCV002314917.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003156102.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 5, 2023 | RCV003419913.4 |
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
(Apr 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mental retardation, X-linked 102
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338460.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: DDX3X c.874C>T (p.Arg292X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: DDX3X c.874C>T (p.Arg292X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 178756 control chromosomes (gnomAD). c.874C>T has been reported in the literature in a female individual affected with X-linked Intellectual Disability (Wang_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446491.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Triangular face (present) , Motor stereotypies (present) , Global developmental delay (present) , Central hypotonia (present) , Hypermetropia (present)
Sex: female
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Pathogenic
(Jul 14, 2020)
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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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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001980687.1
First in ClinVar: Oct 25, 2021 Last updated: Oct 25, 2021 |
Comment:
A heterozygous c.874C>T (p.Arg292Ter) variant in DDX3X was detected in this individual. This nonsense variant found in exon 10 of 17 is predicted to result … (more)
A heterozygous c.874C>T (p.Arg292Ter) variant in DDX3X was detected in this individual. This nonsense variant found in exon 10 of 17 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 reported as a de novo change in a female with developmental delay and/or intellectual disability (PMID: 30349862). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.874C>T (p.Arg292Ter) variant is classified as Pathogenic. (less)
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Pathogenic
(May 09, 2022)
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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: SCV000620988.5
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: 30349862, 32135084, 33084842, 31785789, 33504798) (less)
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
de novo
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845293.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Autistic behavior (present) , Depressed nasal bridge (present) , Epicanthus (present) , Generalized hypotonia (present) , Global developmental delay (present) , Hypotelorism (present) , Intellectual … (more)
Autistic behavior (present) , Depressed nasal bridge (present) , Epicanthus (present) , Generalized hypotonia (present) , Global developmental delay (present) , Hypotelorism (present) , Intellectual disability (present) , Microcephaly (present) , Neonatal hypotonia (present) , Tall stature (present) , Trigonocephaly (present) (less)
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Pathogenic
(Jul 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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DDX3X-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106952.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The DDX3X c.874C>T variant is predicted to result in premature protein termination (p.Arg292*). This variant has been reported as a de novo finding in individuals … (more)
The DDX3X c.874C>T variant is predicted to result in premature protein termination (p.Arg292*). This variant has been reported as a de novo finding in individuals with Snijders Blok type X-linked syndromic intellectual developmental disorder (Wang et al. 2018. PubMed ID: 30349862; Lennox et al. 2020. PubMed ID: 32135084; Martin et al. 2021. PubMed ID: 33504798). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in DDX3X are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Intellectual disability, X-linked 102
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004177235.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Sep 29, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000939481.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DDX3X are known to be pathogenic (PMID: 26235985). This variant has not … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DDX3X are known to be pathogenic (PMID: 26235985). This variant has not been reported in the literature in individuals with DDX3X-related disease. ClinVar contains an entry for this variant (Variation ID: 452201). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg292*) in the DDX3X gene. It is expected to result in an absent or disrupted protein product. (less)
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Pathogenic
(Apr 01, 2023)
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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: SCV004010930.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
DDX3X: PVS1, PM2, PS4:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Mar 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000849278.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R292* pathogenic mutation (also known as c.874C>T), located in coding exon 10 of the DDX3X gene, results from a C to T substitution at … (more)
The p.R292* pathogenic mutation (also known as c.874C>T), located in coding exon 10 of the DDX3X gene, results from a C to T substitution at nucleotide position 874. This changes the amino acid from an arginine to a stop codon within coding exon 10. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Mental retardation, X-linked 102
Affected status: yes
Allele origin:
de novo
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001428217.1
First in ClinVar: Aug 13, 2020 Last updated: Aug 13, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability, X-linked 102
Affected status: unknown
Allele origin:
de novo
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Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University
Accession: SCV003840180.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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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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Phenotypic expansion in DDX3X - a common cause of intellectual disability in females. | Wang X | Annals of clinical and translational neurology | 2018 | PMID: 30349862 |
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 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Text-mined citations for rs1555953488 ...
HelpRecord last updated May 01, 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.