NM_001321075.3(DLG4):c.1489C>T (p.Arg497Ter) AND Intellectual developmental disorder 62

Germline classification:: Pathogenic/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:: RCV001775149.3

Allele description [Variation Report for NM_001321075.3(DLG4):c.1489C>T (p.Arg497Ter)]

NM_001321075.3(DLG4):c.1489C>T (p.Arg497Ter)

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.1489C>T (p.Arg497Ter)

HGVS:

NC_000017.11:g.7193990G>A
NG_008391.2:g.31061C>T
NG_008391.3:g.31060C>T
NM_001128827.4:c.1480C>T
NM_001321074.1:c.1609C>T
NM_001321075.3:c.1489C>TMANE SELECT
NM_001321076.3:c.1309C>T
NM_001321077.3:c.1309C>T
NM_001365.5:c.1618C>T
NM_001369566.3:c.1408C>T
NP_001122299.1:p.Arg494Ter
NP_001308003.1:p.Arg537Ter
NP_001308004.1:p.Arg497Ter
NP_001308005.1:p.Arg437Ter
NP_001308006.1:p.Arg437Ter
NP_001356.1:p.Arg540Ter
NP_001356.1:p.Arg540Ter
NP_001356495.1:p.Arg470Ter
NC_000017.10:g.7097309G>A
NM_001321075.3:c.1489C>T
NM_001365.3:c.1618C>T
NM_001365.4:c.1618C>T
NR_135527.1:n.2819C>T

Protein change:

R437*

Links:

dbSNP: rs1567528092

NCBI 1000 Genomes Browser:

rs1567528092

Molecular consequence:

NR_135527.1:n.2819C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001128827.4:c.1480C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001321074.1:c.1609C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001321075.3:c.1489C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001321076.3:c.1309C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001321077.3:c.1309C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001365.5:c.1618C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369566.3:c.1408C>T - 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
SCV002012041	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002044354	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
SCV003915500	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002012041

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2021)

germline

clinical testing

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

SCV002044354

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]

SCV003915500

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]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research, clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	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

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From 3billion, SCV002012041.1

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

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000620100.1). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002044354.1

#	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, SCV003915500.1

#	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

Last Updated: May 20, 2023

ClinVar

Relating variation to medicine