Submissions for variant NM_002397.5(MEF2C):c.565C>T (p.Arg189Ter)

dbSNP: rs587783747

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146362	SCV000193646	pathogenic	Intellectual disability, autosomal dominant 20	2014-02-04	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000146362	SCV000236514	pathogenic	Intellectual disability, autosomal dominant 20	2014-07-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000578993	SCV000681092	pathogenic	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Identified in a patient with global developmental delay in published literature (Wang et al., 2018); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30376817, 31512412)
Invitae	RCV000146362	SCV001233588	pathogenic	Intellectual disability, autosomal dominant 20	2021-09-24	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with severe intellectual disability, stereotypic movements and hypotonia (PMID: 30376817). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158886). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg189*) in the MEF2C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEF2C are known to be pathogenic (PMID: 20513142).
Revvity Omics, Revvity	RCV000146362	SCV002017257	pathogenic	Intellectual disability, autosomal dominant 20	2021-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000146362	SCV002555971	likely pathogenic	Intellectual disability, autosomal dominant 20	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: MEF2C c.565C>T (p.Arg189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.766C>T [p.Arg256Ter]; c.833del [p.Leu277_Leu278insTer]). The variant was absent in 249200 control chromosomes (gnomAD). c.565C>T has been reported in the literature in at least one individual affected with Rett-Like Intellectual Disability (Wang_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002345453	SCV002652376	pathogenic	Inborn genetic diseases	2018-12-10	criteria provided, single submitter	clinical testing	The p.R189* pathogenic mutation (also known as c.565C>T), located in coding exon 4 of the MEF2C gene, results from a C to T substitution at nucleotide position 565. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was detected in a female with Rett syndrome like symptoms (Wang J et al. BMC Med. Genet., 2018 Oct;19:191). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000146362	SCV004123060	pathogenic	Intellectual disability, autosomal dominant 20	2023-07-01	criteria provided, single submitter	research