ClinVar Genomic variation as it relates to human health
NM_001321075.3(DLG4):c.925C>T (p.Arg309Ter)
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_001321075.3(DLG4):c.925C>T (p.Arg309Ter)
Variation ID: 813881 Accession: VCV000813881.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7196915 (GRCh38) [ NCBI UCSC ] 17: 7100234 (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 1, 2020 Nov 20, 2023 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001321075.3:c.925C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001308004.1:p.Arg309Ter nonsense NM_001128827.4:c.916C>T NP_001122299.1:p.Arg306Ter nonsense NM_001321074.1:c.1045C>T NP_001308003.1:p.Arg349Ter nonsense NM_001321076.3:c.745C>T NP_001308005.1:p.Arg249Ter nonsense NM_001321077.3:c.745C>T NP_001308006.1:p.Arg249Ter nonsense NM_001365.5:c.1054C>T NP_001356.1:p.Arg352Ter nonsense NM_001369566.3:c.844C>T NP_001356495.1:p.Arg282Ter nonsense NR_135527.1:n.2255C>T non-coding transcript variant NC_000017.11:g.7196915G>A NC_000017.10:g.7100234G>A NG_008391.2:g.28136C>T NG_008391.3:g.28135C>T NG_086977.1:g.923G>A - Protein change
- R352*, R349*, R282*, R309*, R249*, R306*
- Other names
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- Canonical SPDI
- NC_000017.11:7196914: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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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
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. |
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DLG4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
141 | 303 | |
LOC126862479 | - | - | - | GRCh38 | - | 57 |
Conditions - Germline
Condition
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 28, 2023 | RCV001004850.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2022 | RCV001171614.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003396590.4 |
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
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
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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
(Nov 05, 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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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001334412.1
First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020 |
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Pathogenic
(Dec 21, 2021)
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criteria provided, single submitter
Method: research
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Intellectual developmental disorder 62
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002044340.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Pathogenic
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder 62
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV002577723.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PVS1;PM6;PM2_supporting
Clinical Features:
Global developmental delay (present) , Macroorchidism (present) , Pectus excavatum (present)
Sex: male
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Pathogenic
(Jun 23, 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: SCV001812167.3
First in ClinVar: Sep 08, 2021 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27479843, 33597769) (less)
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: research
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Intellectual developmental disorder 62
Affected status: yes
Allele origin:
de novo
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Tumer Group, Copenhagen University Hospital, Rigshospitalet
Accession: SCV003915475.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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DLG4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103209.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The DLG4 c.1054C>T variant is predicted to result in premature protein termination (p.Arg352*). This variant has been reported as arising de novo in individuals with … (more)
The DLG4 c.1054C>T variant is predicted to result in premature protein termination (p.Arg352*). This variant has been reported as arising de novo in individuals with intellectual disability (Table S2 in Lelieveld et al. 2016. PubMed ID: 27479843; Rodríguez-Palmero et al. 2021. PubMed ID: 33597769). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in DLG4 are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/813881/). Given the evidence, we interpret c.1054C>T (p.Arg352*) as pathogenic. (less)
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Pathogenic
(Dec 11, 2020)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001164326.2
First in ClinVar: Mar 01, 2020 Last updated: Dec 15, 2020 |
Comment on evidence:
In a patient (patient 747) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1054C-T transition (c.1054C-T, … (more)
In a patient (patient 747) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1054C-T transition (c.1054C-T, NM_001365.3) in the DLG4 gene, resulting in an arg352-to-ter (R352X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. (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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DLG4-related synaptopathy: a new rare brain disorder. | Rodríguez-Palmero A | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33597769 |
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. | Lelieveld SH | Nature neuroscience | 2016 | PMID: 27479843 |
Text-mined citations for rs1182894684 ...
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.