Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MEF2C : complex neurodevelopmental disorder

HGNC:6996 | MONDO_0100038
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 13
Zweier M et al. 2010 Jun (PMID:20513142); Le Meur N et al. 2010 Jan (PMID:19592390); Bienvenu T et al. 2013 Feb (PMID:23001426); Rocha H et al. 2016 Sep (PMID:27255693); Vrečar I et al. 2017 Sep (PMID:28794905); Wang J et al. 2018 Oct 30 (PMID:30376817);
Proband with predicted or proven null variant 1.5 0-2 10 1 0.1 0.1
Paciorkowski AR et al. 2013 May (PMID:23389741);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Leifer D et al. 1993 Feb 15 (PMID:7679508);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Zweier M et al. 2010 Jun (PMID:20513142);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 3 3
Harrington AJ et al. 2016 Oct 25 (PMID:27779093);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4



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 12 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
MEF2C was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2010 (Le Meur et al., 2010 PMID:19592390; Zweier et al., 2010 PMID:20513142). At least 14 unique variants (e.g. missense, nonsense, frameshift, small deletions, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 14 cases, in 7 publications (PMIDs: 19592390, 20513142, 23001426, 23389741, 27255693, 28794905, 30376817). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease appears to be de novo, loss of function. MEF2C is associated with the following disease entities per OMIM: (1) Chromosome 5q14.3 deletion syndrome (MIM:613443); and (2) Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations (MIM:613443). Note that these two disease entities share the same MIM number indicating they may be the same disease. However, per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that the Chromosome 5q14.3 deletion syndrome is a contiguous gene deletion syndrome involving multiple genes of interest beyond MEF2C, including the gene RASA1, exemplifying different molecular mechanisms. Furthermore, the Chromosome 5q14.3 deletion syndrome is associated with a skin phenotype that is not found in individuals with isolated variation in the MEF2C gene. Therefore, we have split into two disease entities; this curation represents the relationship between MEF2C and Complex Neurodevelopmental disorder (MONDO:0100038) (intellectual disability, stereotypic movements, epilepsy, and/or cerebral malformations phenotype) only, in accordance to assertions made in the literature (Paciorkowski et al., 2013 PMID:23389741). This gene-disease association is supported by biochemical function, expression studies, and animal models. In summary, MEF2C is DEFINITIVELY associated with autosomal dominant complex neurodevelopmental disorder. 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 Autism and Intellectual Disability Gene Curation Expert Panel on February 6, 2019 (SOP Version 6).