MEF2C

Chr 5AD

myocyte enhancer factor 2C

Also known as: C5DELq14.3, DEL5q14.3, NEDHSIL

NCBI Gene: 4208 ENSG00000081189 UniProt: Q06413 OMIM: 600662

MEF2C encodes a transcription factor that regulates muscle-specific gene expression and plays crucial roles in cardiac development, neuronal development, and synaptic transmission in the hippocampus and neocortex. Mutations cause autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability, epilepsy, stereotypic hand movements, hypotonia, and impaired language development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.608), and deletions encompassing this locus cause chromosome 5q14.3 deletion syndrome with overlapping features.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family of proteins, which play a role in myogenesis. The encoded protein, MEF2 polypeptide C, has both trans-activating and DNA binding activities. This protein may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disability, stereotypic movements, epilepsy, and cerebral malformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.612 OMIM phenotypes

Clinical Summary— MEF2C

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

132 unique Pathogenic / Likely Pathogenic· 192 VUS of 633 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MEF2C

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.61LOEUF

pLI 0.017

Z-score 2.91

OE 0.32 (0.18–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.95Z-score

OE missense 0.34 (0.29–0.40)

96 obs / 283.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.32 (0.18–0.61)

0≤0.351.4

Missense OE?0.34 (0.29–0.40)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 7 / 21.6Missense obs/exp: 96 / 283.2Syn Z: 1.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMEF2C-related intellectual developmental disorder, stereotypic movements, epilepsy and/or cerebral malformationsLOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.3690th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 59% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFurthermore, dominant-negative mutant proteins of either Gli2 or MEF2C repressed each other's expression, while impairing cardiomyogenesis in P19 EC cells.1

LOFMEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

633 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79

Likely Pathogenic53

VUS192

Likely Benign225

Benign42

Conflicting27

Pathogenic

Likely Pathogenic

192

VUS

225

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	55	9	15	0	79
Likely Pathogenic	23	26	3	1	53
VUS	13	155	21	3	192
Likely Benign	3	16	85	121	225
Benign	1	12	28	1	42
Conflicting	—				27
Total	95	218	152	126	618

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

43 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap MEF2C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →