NM_001321075.3(DLG4):c.1543+2T>C AND Intellectual developmental disorder 62

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Feb 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001004853.12

Allele description [Variation Report for NM_001321075.3(DLG4):c.1543+2T>C]

NM_001321075.3(DLG4):c.1543+2T>C

Gene:

DLG4:discs large MAGUK scaffold protein 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_001321075.3(DLG4):c.1543+2T>C

HGVS:

NC_000017.11:g.7193842A>G
NG_008391.2:g.31209T>C
NG_008391.3:g.31208T>C
NM_001128827.4:c.1534+2T>C
NM_001321074.1:c.1663+2T>C
NM_001321075.3:c.1543+2T>CMANE SELECT
NM_001321076.3:c.1363+2T>C
NM_001321077.3:c.1363+2T>C
NM_001365.5:c.1672+2T>C
NM_001369566.3:c.1462+2T>C
NC_000017.10:g.7097161A>G
NM_001128827.1:c.1534+2T>C
NM_001321075.3:c.1543+2T>C
NM_001365.3:c.1672+2T>C
NM_001365.4:c.1672+2T>C

Nucleotide change:

IVS16DS, T-C, +2

Links:

OMIM: 602887.0006; dbSNP: rs1597444614

NCBI 1000 Genomes Browser:

rs1597444614

Molecular consequence:

NM_001128827.4:c.1534+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001321074.1:c.1663+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001321075.3:c.1543+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001321076.3:c.1363+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001321077.3:c.1363+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001365.5:c.1672+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001369566.3:c.1462+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Intellectual developmental disorder 62
Synonyms:: MENTAL RETARDATION, AUTOSOMAL DOMINANT 62; INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62
Identifiers:: MONDO: MONDO:0032919; MedGen: C5394083; OMIM: 618793

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001164329	OMIM	no assertion criteria provided	Pathogenic (Dec 11, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002044358	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 21, 2021)	germline	research	PubMed (2) [See all records that cite these PMIDs] 33597769, 25741868
SCV003915503	Tumer Group, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 28, 2023)	unknown	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164329

OMIM

no assertion criteria provided

Pathogenic
(Dec 11, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002044358

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 21, 2021)

germline

research

PubMed (2)
[See all records that cite these PMIDs]

SCV003915503

Tumer Group, Copenhagen University Hospital, Rigshospitalet

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 28, 2023)

unknown

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

Moutton S, Bruel AL, Assoum M, Chevarin M, Sarrazin E, Goizet C, Guerrot AM, Charollais A, Charles P, Heron D, Faudet A, Houcinat N, Vitobello A, Tran-Mau-Them F, Philippe C, Duffourd Y, Thauvin-Robinet C, Faivre L.

Clin Genet. 2018 Jun;93(6):1172-1178. doi: 10.1111/cge.13243. Epub 2018 Apr 14.

PubMed [citation]

PMID:: 29460436

Rodríguez-Palmero A, Boerrigter MM, Gómez-Andrés D, Aldinger KA, Marcos-Alcalde Í, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogné B, Coubes C, de Man SA, Denommé-Pichon AS, Dye TJ, Elmslie F, Feuk L, et al.

Genet Med. 2021 May;23(5):888-899. doi: 10.1038/s41436-020-01075-9. Epub 2021 Feb 17.

PubMed [citation]

PMID:: 33597769

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV001164329.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 35-year-old man (patient 3) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a heterozygous T-to-C transition (c.1672+2T-C, NM_001365.3) in intron 16 of the DLG4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. The variant was not found in the mother; DNA from the father was unavailable. Analysis of patient cells showed that the mutation caused aberrant splicing predicted to result in a frameshift and premature termination (Gly558ProfsTer37). This change would cause disruption of the guanylate kinase domain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002044358.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Tumer Group, Copenhagen University Hospital, Rigshospitalet, SCV003915503.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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