Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MED12 : MED12-related intellectual disability syndrome

HGNC:11957 | MONDO_0100000
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Deciphering Developmental Disorders Study et al. 2015 Mar 12 (PMID:25533962);
Proband with predicted or proven null variant 1.5 0-2 10 0.5 0.5
Lesca G et al. 2013 Dec (PMID:24039113);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Schwartz CE et al. 2007 Jul (PMID:17369503); Risheg H et al. 2007 Apr (PMID:17334363); Lyons MJ et al. 2009 Jan (PMID:18805826); Clark RD et al. 2009 Nov (PMID:19938245); Rump P et al. 2011 Feb (PMID:20507344); Vulto-van Silfhout AT et al. 2013 Mar 7 (PMID:23395478); Tzschach A et al. 2015 Nov (PMID:25649377); Langley KG et al. 2015 Dec (PMID:26338144); Yamamoto T et al. 2015 Jun 18 (PMID:27081531); Prontera P et al. 2016 Sep (PMID:27312080); Caro-Llopis A et al. 2016 Dec (PMID:27500536); Narayanan DL et al. 2017 Aug (PMID:28544239); Patil SJ et al. 2017 Sep (PMID:28794916); Prescott TE et al. 2016 Aug (PMID:27286923); Callier P et al. 2013 Dec (PMID:23506379); Graham JM et al. 2008 Dec 1 (PMID:18973276); Fieremans N et al. 2016 Aug (PMID:27159028); Hu H et al. 2009 Dec (PMID:21836662); Popp B et al. 2017 Dec (PMID:29158550); Donnio LM et al. 2017 Jun 1 (PMID:28369444);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 8.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2 0.5
Kim S et al. 2006 May 19 (PMID:16565090);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 0.5
Donnio LM et al. 2017 Jun 1 (PMID:28369444);
Models Non-human model organism 2 0 - 4 4 2
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Hong SK et al. 2005 Dec 20 (PMID:16344459);
Rescue in cell culture model 1 0 - 2 1
Vulto-van Silfhout AT et al. 2013 Mar 7 (PMID:23395478);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 8.5 3 11.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
True total score is 14.5 with additional LOD scoring counted by original curator 3(8.74*).
OMIM: Lujan-Fryns Syndrome (MIM:309520) Ohdo Syndrome, X-Linked (MIM:300895) Opitz-Kaveggia Syndrome (MIM:305450) Orphanet: Blepharophimosis-Intellectual Disability Syndrome, MKB Type (ORPHA:293707) FG Syndrome Type 1 (ORPHA:93932) X-Linked Intellectual Disability with marfanoid habitus (ORPHA:776) X-linked non-syndromic intellectual disability (ORPHA:777). The MED12 gene is associated with several disease entities in which all phenotypes occur within the spectrum of X-Linked Syndromic Intellectual Disability (ID). This association was made using case-level data only. Fifteen unique variants segregating in males (14 missense, 1 in-frame indel) and 1 de novo nonsense variant in a female proband have been reported. Female carriers of the MED12 variants can show mild ID and/or facial dysmorphism. MED12 was first associated with this disease in humans in 2007 (Rising et. al). This gene-disease association is supported by functional assays and animal models. In summary, MED12 is definitively associated with X-Linked MED12-related Intellectual Disability Syndrome. This classification was approved by the Intellectual Disability/Autism Gene Curation Expert Panel using the ClinGen Clinical Validity Framework on 04/18/2018. Lumping and Splitting : Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern underlying the disease entities: (1) Lujan-Fryns Syndrome (MIM:309520), (2) Ohdo Syndrome (MIM:300895), and (3) Opitz-Kaveggia (FG) Syndrome (MIM:305450). Therefore the entities (MIM:309520, MIM:300895, MIM:305450) have been lumped into one disease entity, X-Linked MED12-related Intellectual Disability Syndrome.