ClinGen Dosage Sensitivity Curation Page

MED12

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
24039113 Lesca et al. 2013 identified a c.5898dupC mutation causing p.Ser1967GlnfsX84 segregating in one family with non-syndromic intellectual disability (ID) in 9 affected males. There were 10 carrier females, seven with variable cognitive impairment including 1 with significant ID. Expression studies performed produced two abnormal mRNAs (one with the frameshift and the other one with an in-frame 75-bp deletion due to the activation of two cryptic splice sites in exon 41), and therefore escaped non-sense-mediated RNA decay. It is unclear if this mutation would be consistent with haploinsufficiency.

Haploinsufficiency phenotype comments:

No clear loss of function mutations have been described in MED12. Missense mutations have been associated with three different established XLR disorders: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and Ohdo syndrome. In addition, missense mutations have also been observed in individuals with non-syndromic X-linked Intellectual disability (p.R521H) (Fieremans 2016), (p.R621Q) (Prescott 2016), (p.I771T) (Prontera 2016), (p.R815Q) (Tzschach 2015), (p.I1023V) (Yamamoto 2015) (p.A1383T) (Langley 2015) and (p.E1974H) (Bouazzi 2015). The disease mechanism of some missense mutations do not appear to be loss of function. Donnio 2017: PMID: 28369444.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.