Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_002397.5(MEF2C):c.9A>T(p.Arg3Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
MEF2C (HGNC:6996): (myocyte enhancer factor 2C) 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]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a domain MADS-box (size 54) in uniprot entity MEF2C_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002397.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MEF2C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.9523 (above the threshold of 3.09). Trascript score misZ: 4.8218 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 20, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
Variant 5-88823780-T-A is Pathogenic according to our data. Variant chr5-88823780-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 218315.Status of the report is no_assertion_criteria_provided, 0 stars.
Centro Hospitalar S Joao, Faculty of Medicine of Porto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
This variant in the MEF2C gene, not described in the literature before, was identified in a 10 year-old boy with severe psychomotor delay, epilepsy, generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphism. This variant is predicted to be pathogenic (according to Mutation taster (MT), PolyPhen-2 (PP-2) and Sorts Intolerant From Tolerant (SIFT). -
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