NM_001321075.3(DLG4):c.1878C>A (p.Cys626Ter) AND Intellectual developmental disorder 62

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 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:: RCV001800214.3

Allele description

NM_001321075.3(DLG4):c.1878C>A (p.Cys626Ter)

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.1878C>A (p.Cys626Ter)

HGVS:

NC_000017.11:g.7191991G>T
NG_008391.2:g.33060C>A
NG_008391.3:g.33059C>A
NM_001128827.3:c.1869C>A
NM_001128827.4:c.1869C>A
NM_001321074.1:c.1998C>A
NM_001321075.3:c.1878C>AMANE SELECT
NM_001321076.3:c.1698C>A
NM_001321077.3:c.1698C>A
NM_001365.5:c.2007C>A
NM_001369566.3:c.1797C>A
NP_001122299.1:p.Cys623Ter
NP_001308003.1:p.Cys666Ter
NP_001308004.1:p.Cys626Ter
NP_001308005.1:p.Cys566Ter
NP_001308006.1:p.Cys566Ter
NP_001356.1:p.Cys669Ter
NP_001356.1:p.Cys669Ter
NP_001356495.1:p.Cys599Ter
NC_000017.10:g.7095310G>T
NM_001321075.1:c.1878C>A
NM_001321075.3:c.1878C>A
NM_001365.4:c.2007C>A

Protein change:

C566*

Links:

dbSNP: rs1451196379

NCBI 1000 Genomes Browser:

rs1451196379

Molecular consequence:

NM_001128827.4:c.1869C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001321074.1:c.1998C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001321075.3:c.1878C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001321076.3:c.1698C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001321077.3:c.1698C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001365.5:c.2007C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001369566.3:c.1797C>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV002044368	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2021)	de novo	research	PubMed (2) [See all records that cite these PMIDs] 33597769, 25741868
SCV002559223	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003915519	Tumer Group, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 28, 2023)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV004037363	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2020)	de novo	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27479843, 29460436, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	no	clinical testing, research

Citations

PubMed

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

Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.

Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Löhner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C.

Nat Neurosci. 2016 Sep;19(9):1194-6. doi: 10.1038/nn.4352. Epub 2016 Aug 1. Review.

PubMed [citation]

PMID:: 27479843

See all PubMed Citations (4)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002044368.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV002559223.1

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

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

From Tumer Group, Copenhagen University Hospital, Rigshospitalet, SCV003915519.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center, SCV004037363.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	clinical testing	PubMed (3)

Description

The c.1869C>A (p.Cys623Ter) variant in the DLG4 gene substitutes a cysteine residue to a stop codon at amino acid 623 in the guanylate kinase catalytic domain in coding exon 20 (out of 22 coding exons in total) of the DLG4 gene. This change results in premature protein truncation and is predicted to undergo nonsense mediated mRNA decay (NMD) Analyses of parental samples shows that neither the mother (PGL20-971_C1) nor the father (PGL20-971_C2) harbor this variant. Therefore, the variant appears to be a de novo change. This variant is absent in the Genome Aggregation Database (gnomAD), indicating that it is not a common benign variant in the populations represented therein. Heterozygous loss of function variants in DLG4 have been observed in multiple individuals with clinical features of Intellectual Developmental Disorder 62 (PMIDs: 27479843, 29460436). To the best of our knowledge this exact variant has not been reported in the literature or in ClinVar, however loss of function variants downstream of p.Cys623Ter have been reported to be disease causing.

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

Last Updated: Dec 30, 2023

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