The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.63). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33597769). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001164039). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_001321075.3(DLG4):c.1083G>A (p.Ser361=)
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.
(7)
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001321075.3(DLG4):c.1083G>A (p.Ser361=)
Variation ID: 1164039 Accession: VCV001164039.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7196757 (GRCh38) [ NCBI UCSC ] 17: 7100076 (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 Jun 24, 2021 Nov 17, 2024 Jun 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001321075.3:c.1083G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001308004.1:p.Ser361= synonymous NM_001365.5:c.1212G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001356.1:p.Ser404= synonymous NM_001128827.4:c.1074G>A NP_001122299.1:p.Ser358= synonymous NM_001321074.1:c.1203G>A NP_001308003.1:p.Ser401= synonymous NM_001321076.3:c.903G>A NP_001308005.1:p.Ser301= synonymous NM_001321077.3:c.903G>A NP_001308006.1:p.Ser301= synonymous NM_001365.3:c.1212G>A NM_001369566.3:c.1002G>A NP_001356495.1:p.Ser334= synonymous NR_135527.1:n.2413G>A non-coding transcript variant NC_000017.11:g.7196757C>T NC_000017.10:g.7100076C>T NG_008391.2:g.28294G>A NG_008391.3:g.28293G>A NG_086977.1:g.765C>T - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000017.11:7196756:C:T
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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. |
|||
| DLG4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
163 | 336 | |
| LOC126862479 | - | - | - | GRCh38 | - | 61 |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 5, 2024 | RCV001527313.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003313227.1 |
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
(Dec 21, 2021)
|
criteria provided, single submitter
Method: research
|
Intellectual developmental disorder 62
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002044345.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
|
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual developmental disorder 62
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841656.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.63). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33597769). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001164039). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Tall stature (present) , Thoracic kyphosis (present) , Lumbar scoliosis (present) , Hypermetropia (present) , Osteopenia (present) , Pes cavus … (more)
Global developmental delay (present) , Tall stature (present) , Thoracic kyphosis (present) , Lumbar scoliosis (present) , Hypermetropia (present) , Osteopenia (present) , Pes cavus (present) , Joint laxity (present) , Genu recurvatum (present) , Elevated circulating growth hormone concentration (present) , Mandibular prognathia (present) (less)
|
|
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Likely pathogenic
(Feb 28, 2023)
|
criteria provided, single submitter
Method: research
|
Intellectual developmental disorder 62
Affected status: yes
Allele origin:
de novo
|
Tumer Group, Copenhagen University Hospital, Rigshospitalet
Accession: SCV003915485.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
|
Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004012397.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Comment:
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence … (more)
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33597769, 34580403) (less)
|
|
|
Likely Pathogenic
(Jun 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual developmental disorder 62
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397751.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1212 of the coding sequence of the DLG4 gene. Though this is a synonymous … (more)
This sequence variant is a single nucleotide substitution (G>A) at position 1212 of the coding sequence of the DLG4 gene. Though this is a synonymous change that does not alter residue coded by the Ser404 codon, this nucleotide change may impact splicing. This is a previously reported variant (ClinVar 1164039) that has been observed as de novo in an individual affected by global developmental delay, autism, hypotonia, strabismus, and joint laxity (PMID: 33597769). This variant is absent from the gnomAD v4.1.0 population database (0/1602318 alleles). In silico tools suggest this variant will cause aberrant splicing through disruption of the exon 11 splice donor site, and the G at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP3, PS2 (less)
|
|
|
Pathogenic
(May 13, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual developmental disorder 62
Affected status: yes
Allele origin:
de novo
|
Pediatric Genetics Clinic, Sheba Medical Center
Accession: SCV001712171.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Clinical Features:
Global developmental delay (present) , Self-injurious behavior (present) , Sleep abnormality (present) , High palate (present) , Widely spaced teeth (present) , Brachydactyly (present) , … (more)
Global developmental delay (present) , Self-injurious behavior (present) , Sleep abnormality (present) , High palate (present) , Widely spaced teeth (present) , Brachydactyly (present) , Joint hypermobility (present) , Hypotonia (present) (less)
Secondary finding: no
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual developmental disorder 62
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001737973.1
First in ClinVar: Jun 24, 2021 Last updated: Jun 24, 2021 |
Sex: female
|
Comment:
Comment:
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33597769, 34580403)
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1212 of the coding sequence of the DLG4 gene. Though this is a synonymous change that does not alter residue coded by the Ser404 codon, this nucleotide change may impact splicing. This is a previously reported variant (ClinVar 1164039) that has been observed as de novo in an individual affected by global developmental delay, autism, hypotonia, strabismus, and joint laxity (PMID: 33597769). This variant is absent from the gnomAD v4.1.0 population database (0/1602318 alleles). In silico tools suggest this variant will cause aberrant splicing through disruption of the exon 11 splice donor site, and the G at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP3, PS2
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:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.63). The variant has been previously reported as de novo in a similarly affected individual (PMID: 33597769). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001164039). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33597769, 34580403)
Comment:
This sequence variant is a single nucleotide substitution (G>A) at position 1212 of the coding sequence of the DLG4 gene. Though this is a synonymous change that does not alter residue coded by the Ser404 codon, this nucleotide change may impact splicing. This is a previously reported variant (ClinVar 1164039) that has been observed as de novo in an individual affected by global developmental delay, autism, hypotonia, strabismus, and joint laxity (PMID: 33597769). This variant is absent from the gnomAD v4.1.0 population database (0/1602318 alleles). In silico tools suggest this variant will cause aberrant splicing through disruption of the exon 11 splice donor site, and the G at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP3, PS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
Text-mined citations for rs1227093654 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 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.