MED13L

protein-coding

mediator complex subunit 13L, the group of MicroRNA protein coding host genes|Mediator complex

Gene summary

The protein encoded by this gene is a subunit of the Mediator complex, a large complex of proteins that functions as a transcriptional coactivator for most RNA polymerase II-transcribed genes. The encoded protein is involved in early development of the heart and brain. Defects in this gene are a cause of transposition of the great arteries, dextro-looped (DTGA).[provided by RefSeq, Jul 2010]

Previous symbols:

THRAP2

MANE transcript

NM_015335.5

Inheritance

AD, AR

ClinVar variants

P:324U:648B:585

Top phenotype

Impaired intellectual development and distinctive facial features with or without cardiac defects

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr12:115,957,905-116,277,693

External References & Databases

Ensembl (ENSG00000123066)

Transcript & Mutation Effects

hg38 • Region Span ~319.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiac anomalies - developmental delay - facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014773

Submitter: Orphanet

cardiac anomalies - developmental delay - facial dysmorphism syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014773

Submitter: G2P

cardiac anomalies - developmental delay - facial dysmorphism syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014773

Submitter: Labcorp Genetics (formerly Invitae)

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Intragenic deletions in *MED13L* were first reported in patients with autosomal dominant syndromic intellectual disability in 2013 (Asadollahi et al., PMID: 23403903). Individuals with loss-of-function (LoF) variants in *MED13L* present with moderate to severe intellectual disability, muscular hypotonia and facial anomalies (PMIDs: 28645799, 29511999). Additional features observed in 20%-50% of patients include severe speech delay, abnormal brain MRI, ataxia, and autistic features; cardiac anomalies have been reported in about 17% of patients (PMIDs: 28645799, 29511999). De novo LoF variants, including large intragenic deletions, nonsense, frameshift and splice site variants have been reported in over 30 probands in five publications (PMIDs: 23403903, 24781760, 25712080, 27500536, 29511999). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. At least 13 individuals with de novo missense variants presented with similar but more severe phenotypes and with a higher frequency of seizures than observed in patients with LoF variants (PMIDs: 24896178, 27500536, 28645799, 29511999, 29593475, 32646507). Probands with a missense variant were not counted towards genetic evidence since functional data supporting pathogenicity of missense variants was not available. The mechanism of pathogenicity is haploinsufficiency (PMIDs: 23403903, 25137640). This gene-disease relationship is also supported by a zebrafish model, rescue experiments, protein interaction, and biochemical function. In summary, there is definitive evidence supporting the relationship between *MED13L* and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 21, 2021 (SOP Version 8).

cardiac anomalies - developmental delay - facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014773

Submitter: Illumina

The MED13L gene is located on chromosome 12 at 12q24.21 and encodes the mediator complex subunit 13L protein. MED13L is part of the CDK8 module of the Mediator complex, which is required for gene transcription by RNA polymerase II (24550107: Yin & Wang (2014). The MED13L gene was first reported in relation to MED13L-related neurodevelopmental disorder in 2013 (23403903: Asadollahi et al. (2013). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least seven variants have been reported in seven cases from three publications, including two frameshift, three nonsense, one missense, and one in-frame deletion (25712080: Cafiero et al. 2015; 29740699: Snijders Blok et al. 2018; 29959045: Tørring et al. 2019). All variants from these cases were confirmed to have occurred de novo. Considerably more case level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of disease is haploinsufficiency. This gene-disease relationship is supported by the biochemical function of MED13L as a component of the Mediator complex, which is required for gene transcription by RNA polymerase II (24550107: Yin & Wang 2014). Knockdown of the MED13L zebrafish ortholog med13b resulted in craniofacial, brain, and eye abnormalities, and the zebrafish phenotype could be rescued by co-expression of human MED13L (25137640: Utami et al. 2014). Suppression of MED13L with shRNA in ES-derived human neural progenitor cells that were differentiated into neurons demonstrated that MED13L regulates transcription of many genes, including those in the Wnt and FGF pathways that are critical for craniofacial and brain development (25137640: Utami et al. 2014). In summary, MED13L is definitively associated with MED13L-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*MED13L* was first reported in relation to autosomal dominant congenital heart disease in 2003 (Muncke et al. 2003, PMID: 14638541). Only one missense variant that was reported as a de novo occurrence in an individual with congenital heart disease was included in this curation (PMID: 32368696). There were several other probands reported with variants in *MED13L*, however they were not scored due to high minor allele frequency in gnomAD v4 (MAF> 0.00001, PMIDs: 14638541, 27959697, 33448881, 35885997, 36307859, 35910219). This gene-disease relationship is also supported by an expression study (PMID: 14638541). In summary, there is limited evidence supporting the relationship between *MED13L* and autosomal dominant congenital heart disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 2/12/2024 (SOP Version 10).

cardiac anomalies - developmental delay - facial dysmorphism syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014773

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Impaired intellectual development and distinctive facial features with or without cardiac defectsAD/AR

Manifestation: Cardiovascular; Craniofacial; Neurologic

Intervention: Cardiovascular

Rationale: Among other features, the condition may involve congenital cardiac anomalies, some of which may be subtle or occult, and which may benefit from surveillance and/or interventions to ameliorate sequelae

Refs: 14638541; 21937992; 23403903; 24781760; 25137640; 25356899; 25712080; 25758992

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED13L variants in ClinVar

27 Conditions Cataloged

Dextro-looped transposition of the great arteriesTotal: 934

not providedTotal: 547

Cardiac anomalies - developmental delay - facial dysmorphism syndromeTotal: 310

Inborn genetic diseasesTotal: 256

MED13L-related disorderTotal: 128

not specifiedTotal: 83

Intellectual disabilityTotal: 26

See casesTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015335.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	277 clinvar	35 clinvar	318
missense	3 clinvar	46 clinvar	627 clinvar	228 clinvar	43 clinvar	947
nonsense	61 clinvar	23 clinvar	2 clinvar			86
start loss	1 clinvar	2 clinvar				3
frameshift	104 clinvar	51 clinvar	3 clinvar			158
splice donor/acceptor (+/-2bp)	17 clinvar	16 clinvar	10 clinvar	1 clinvar	1 clinvar	45
Total	186	138	648	506	79	1557

Highest pathogenic variant AF is 0.0013150178

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015335.5	RefSeq	NP_056150.1	31	MANE Select
ENST00000281928.9	Ensembl	ENSP00000281928.3	31	MANE Select
ENST00000548743.2	Ensembl	ENSP00000448553.2	17	Standard
ENST00000549786.2	Ensembl	ENSP00000446782.2	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
Developmental Biology
Transcriptional regulation of white adipocyte differentiation

Biological Process

regulation of transcription by RNA polymerase II

Molecular Function

transcription coregulator activity

Cellular Component

mediator complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281928
Coding exons: 31
Length: 319433
Individuals with no LoFs: 125615
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125628
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.69	839	1.20e+3	0.700	0.0000686	14509
Missense (PolyPhen)		100	212.31	0.471		2560
Synonymous	-0.196	463	458	1.01	0.0000277	4387
Loss of Function	9.01	2	98.5	0.0203	0.00000509	1150

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.000054	0.000046	rare
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0.000038	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.;
Disease: DISEASE: Note=A chromosomal aberration involving MED13L is found in a patient with transposition of the great arteries, dextro- looped and mental retardation. Translocation t(12;17)(q24.1;q21). {ECO:0000269|PubMed:14638541}.; DISEASE: Mental retardation and distinctive facial features with or without cardiac defects (MRFACD) [MIM:616789]: An autosomal dominant, syndromic form of mental retardation characterized by delayed psychomotor development, profound language impairment, and facial dysmorphism, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:24781760, ECO:0000269|PubMed:25167861, ECO:0000269|PubMed:25356899, ECO:0000269|PubMed:25712080, ECO:0000269|PubMed:25758992}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.0362
RVIS EVS: -2.74
RVIS percentile EVS: 0.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.905

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium