MED23

Chr 6AR

mediator complex subunit 23

Also known as: ARC130, CRSP130, CRSP133, CRSP3, DRIP130, MRT18, SUR-2, SUR2

NCBI Gene: 9439 ENSG00000112282 UniProt: Q9ULK4 OMIM: 605042

The MED23 protein is a subunit of the CRSP cofactor complex required for SP1-mediated gene transcription activation and also functions as a component of thyroid hormone receptor-associated protein complexes that facilitate transcription initiation by RNA polymerase II. Biallelic mutations cause autosomal recessive intellectual developmental disorder-18, with or without epilepsy. The pathogenic mechanism involves disrupted transcriptional regulation due to loss of cofactor function in gene activation processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.501 OMIM phenotype

Clinical Summary— MED23

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

68 unique Pathogenic / Likely Pathogenic· 197 VUS of 487 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.50LOEUF

pLI 0.000

Z-score 5.09

OE 0.36 (0.27–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.73Z-score

OE missense 0.51 (0.47–0.55)

369 obs / 728.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.36 (0.27–0.50)

0≤0.351.4

Missense OE?0.51 (0.47–0.55)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 27 / 74.4Missense obs/exp: 369 / 728.1Syn Z: 1.21

ClinVar Variant Classifications

487 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic39

VUS197

Likely Benign176

Benign4

Conflicting3

Pathogenic

Likely Pathogenic

197

VUS

176

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	6	3	0	29
Likely Pathogenic	35	3	1	0	39
VUS	5	180	11	1	197
Likely Benign	1	3	68	104	176
Benign	0	0	4	0	4
Conflicting	—				3
Total	61	192	87	105	448

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap MED23 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →