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Intellectual disability

Gene: SET

Green List (high evidence)
SET (SET nuclear proto-oncogene)
EnsemblGeneIds (GRCh38): ENSG00000119335
EnsemblGeneIds (GRCh37): ENSG00000119335
OMIM: 600960, Gene2Phenotype
SET is in 3 panels

4 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Amber to Green: Sufficient (>3) cases to support ID causation as noted in the review by Konstantinos Varvagiannis: 5 families (6 individuals) reported in PMID:29688601 (Stevens et al., 2018), plus 3 ID patients in the DDD study (PMID:28135719), including the variant found in the mother and son in PMID:29688601. Plus the large scale PMID:25356899 (Hamdan et al 2014) study.
Created: 14 Feb 2019, 1:14 p.m.
Created: 14 Feb 2019, 1:14 p.m.

Panel version: 2.634

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous mutations in SET cause Mental retardation, autosomal dominant 58 (MIM 618106).

PMID: 29688601 reports on 6 individuals from 5 families with pathogenic variants in SET, all investigated for intellectual disability.

In 5 of these patients the variant had occurred as a de novo event while a single individual had inherited a frameshift mutation from his similarly affected mother (also included in the study). The authors note that 4 additional patients had previously been reported by Hamdan et al. (PMID: 25356899) as well as the DDD study (PMID: 28135719).

DD/ID was an almost universal feature.

In total 2 missense and 5 loss-of-function (LoF) variants have been observed.

The gene appears to be intolerant to LoF mutations (pLI of 0.96) and is likely to exhibit haploinsuffiency (HI index of 2.03). Additionally it is rather depleted in missense variants (Z-score of 3.11).

SET has 4 isoforms which differ only in the coding sequence for exon 1. The authors note that the variants reported in the patients affect all 4 isoforms while variants present in public databases (ExAC/gnomAD) affect only single isoforms (their first exon).

Overall haploinsufficiency is promoted as the underlying mechanism (with the 2 missense variants possibly abolishing histone and dsDNA binding properties of SET).

Functional studies have not been performed by the authors. However several lines of evidence are provided concerning the function of SET and its important role in neurogenesis.

SET is included in gene panels for intellectual disability offered by diagnostic laboratories.

As a result, this gene can be considered for upgrade to green.
Created: 5 Dec 2018, 8:45 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Mental retardation, autosomal dominant 58 (MIM 618106)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 5 Dec 2018, 8:45 p.m.

Panel version: 2.574

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NA
Created: 27 Jul 2017, 8:21 p.m.

Mode of inheritance
Unknown

Publications

Created: 2 Aug 2017, 10:24 p.m.

Panel version: 1.354

Louise Daugherty (Genomics England Curator)

I don't know

Gene found to be of significance (P < 7 × 10−7) and confirmed in the Deciphering Developmental Disorders Study paper (PMID:28135719)
Created: 29 Nov 2017, 2:10 p.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.
Created: 28 Jul 2017, 3:53 p.m.

Mode of inheritance
Unknown

Phenotypes
Intellectual disability

Publications

Created: 28 Jul 2017, 3:53 p.m.

Panel version: 1.465

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Intellectual disability
  • SET syndrome
  • Mental retardation, autosomal dominant 58, 618106
OMIM
600960
Clinvar variants
Variants in SET
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

14 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: set has been classified as Green List (High Evidence).

14 Feb 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SET were changed from Intellectual disability; SET syndrome to Intellectual disability; SET syndrome; Mental retardation, autosomal dominant 58, 618106

29 Sep 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to SET.

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 2

Set mode of inheritance, Set publications

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene SET was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene SET was set to ['28135719']

28 Jul 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

27 Jul 2017, Gel status: 0

Added New Source

BRIDGE consortium (NIHRBR-RD)

SET was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene

27 Jul 2017, Gel status: 0

Created

BRIDGE consortium (NIHRBR-RD)

SET was created by BRIDGE