MED12L

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: ClinGen

The *MED12L* gene is located on chromosome 3 at 3q25.1 and encodes for the 2145-amino acid mediator complex subunit 12-like (MED12L) protein, one of the subunits in the CDK8 kinase module of the Mediator complex.. The Mediator complex is a large multiprotein complex consisting of four different modules (Head, Middle, Tail and CDK8 kinase) and 26 subunits. The Mediator complex plays a key regulator of gene expression involved in cell growth, homeostasis, development and differentiation. *MED12L* was first reported in relation to autosomal dominant Nizon-Isidor syndrome in 2019 (Nizon et al 2019, PMID: 31155615). Evidence supporting this gene-disease relationship includes case-level and experimental data. Six heterozygous variants (1 missense, 1 nonsense, 2 frameshift, and 2 splice-site variants) in *MED12L* that have been reported in at least 9 unrelated patients with clinical features suggestive of autosomal dominant Nizon-Isidor syndrome in 3 publications (Nizon et al 2019, PMID: 31155615; Park et al 2022, PMID: 36212160; Ferraz et al 2022, PMID: 35920825) are included in this curation. This gene-disease relationship is also supported by biochemical function, gene expression studies, and protein interaction data (Maalouf et al 2024, PMID: 38943827; Daniels et al 2013; Vogl et al 2013, PMID:23575864). In summary, there is definitive evidence supporting the relationship between *MED12L* and autosomal dominant Nizon-Isidor syndrome. 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 Syndromic Disorders GCEP on the meeting date November 19th, 2024 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0030030

Submitter: Illumina

MED12L was first reported in relation to autosomal dominant Nizon-Isidor syndrome in 2019 (31155615: Nizon et al. 2019). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least four probands in one publication (31155615: Nizon et al. 2019). The four variants were all predicted loss of function and included a frameshift, a stop gained and two splice variants and at least two occurred de novo. This gene-disease relationship is supported by expression data and protein interaction data; MED12L is a component of the kinase module of the Mediator complex, other subunits of the kinase module have also been implicated in intellectual disability, including MED12, MED13L, MED13 and CDK19 (28778422: Jeronimo et al. 2017). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.