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)
ClinVar Genomic variation as it relates to human health
NM_002397.5(MEF2C):c.565C>T (p.Arg189Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002397.5(MEF2C):c.565C>T (p.Arg189Ter)
Variation ID: 158886 Accession: VCV000158886.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q14.3 5: 88751881 (GRCh38) [ NCBI UCSC ] 5: 88047698 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 Oct 8, 2024 Jul 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002397.5:c.565C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002388.2:p.Arg189Ter nonsense NM_001131005.2:c.559C>T NP_001124477.1:p.Arg187Ter nonsense NM_001193347.1:c.619C>T NP_001180276.1:p.Arg207Ter nonsense NM_001193348.1:c.421C>T NP_001180277.1:p.Arg141Ter nonsense NM_001193349.3:c.421C>T NP_001180278.1:p.Arg141Ter nonsense NM_001193350.2:c.565C>T NP_001180279.1:p.Arg189Ter nonsense NM_001308002.3:c.565C>T NP_001294931.1:p.Arg189Ter nonsense NM_001363581.2:c.565C>T NP_001350510.1:p.Arg189Ter nonsense NM_001364329.2:c.565C>T NP_001351258.1:p.Arg189Ter nonsense NM_001364330.2:c.565C>T NP_001351259.1:p.Arg189Ter nonsense NM_001364331.2:c.565C>T NP_001351260.1:p.Arg189Ter nonsense NM_001364332.2:c.421C>T NP_001351261.1:p.Arg141Ter nonsense NM_001364333.2:c.565C>T NP_001351262.1:p.Arg189Ter nonsense NM_001364334.2:c.565C>T NP_001351263.1:p.Arg189Ter nonsense NM_001364335.2:c.565C>T NP_001351264.1:p.Arg189Ter nonsense NM_001364336.2:c.565C>T NP_001351265.1:p.Arg189Ter nonsense NM_001364337.2:c.565C>T NP_001351266.1:p.Arg189Ter nonsense NM_001364338.2:c.619C>T NP_001351267.1:p.Arg207Ter nonsense NM_001364339.2:c.565C>T NP_001351268.1:p.Arg189Ter nonsense NM_001364340.2:c.565C>T NP_001351269.1:p.Arg189Ter nonsense NM_001364341.2:c.565C>T NP_001351270.1:p.Arg189Ter nonsense NM_001364342.2:c.565C>T NP_001351271.1:p.Arg189Ter nonsense NM_001364343.2:c.559C>T NP_001351272.1:p.Arg187Ter nonsense NM_001364344.2:c.421C>T NP_001351273.1:p.Arg141Ter nonsense NM_001364345.2:c.565C>T NP_001351274.1:p.Arg189Ter nonsense NM_001364346.2:c.565C>T NP_001351275.1:p.Arg189Ter nonsense NM_001364347.2:c.565C>T NP_001351276.1:p.Arg189Ter nonsense NM_001364348.2:c.565C>T NP_001351277.1:p.Arg189Ter nonsense NM_001364349.2:c.565C>T NP_001351278.1:p.Arg189Ter nonsense NM_001364350.2:c.565C>T NP_001351279.1:p.Arg189Ter nonsense NM_001364352.2:c.559C>T NP_001351281.1:p.Arg187Ter nonsense NM_001364353.2:c.187C>T NP_001351282.1:p.Arg63Ter nonsense NM_001364354.2:c.421C>T NP_001351283.1:p.Arg141Ter nonsense NM_001364355.2:c.421C>T NP_001351284.1:p.Arg141Ter nonsense NM_001364356.2:c.187C>T NP_001351285.1:p.Arg63Ter nonsense NM_001364357.2:c.139C>T NP_001351286.1:p.Arg47Ter nonsense NC_000005.10:g.88751881G>A NC_000005.9:g.88047698G>A NG_023427.1:g.157225C>T - Protein change
- R187*, R189*, R141*, R207*, R63*, R47*
- Other names
- -
- Canonical SPDI
- NC_000005.10:88751880:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MEF2C | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
463 | 574 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2023 | RCV000146362.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 22, 2019 | RCV000578993.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2018 | RCV002345453.2 | |
|
MEF2C-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 20, 2024 | RCV004734705.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193646.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Apr 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000681092.3
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023 |
Comment:
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); … (more)
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) (less)
|
|
|
Pathogenic
(Jul 09, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations
Affected status: yes
Allele origin:
de novo
|
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236514.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
|
|
|
Likely pathogenic
(Jun 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 20
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555971.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jun 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 20
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017257.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 20
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001233588.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Dec 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002652376.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Intellectual disability, autosomal dominant 20
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123060.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
|
Pathogenic
(May 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
MEF2C-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005341903.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The MEF2C c.565C>T variant is predicted to result in premature protein termination (p.Arg189*). This variant has been reported to be causative for MEF2C-related disorders, and … (more)
The MEF2C c.565C>T variant is predicted to result in premature protein termination (p.Arg189*). This variant has been reported to be causative for MEF2C-related disorders, and has been documented as a de novo finding in multiple cases (Wang et al. 2018. PubMed ID: 30376817; https://www.ncbi.nlm.nih.gov/clinvar/variation/158886/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MEF2C are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
The MEF2C c.565C>T variant is predicted to result in premature protein termination (p.Arg189*). This variant has been reported to be causative for MEF2C-related disorders, and has been documented as a de novo finding in multiple cases (Wang et al. 2018. PubMed ID: 30376817; https://www.ncbi.nlm.nih.gov/clinvar/variation/158886/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MEF2C are expected to be pathogenic. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
The MEF2C c.565C>T variant is predicted to result in premature protein termination (p.Arg189*). This variant has been reported to be causative for MEF2C-related disorders, and has been documented as a de novo finding in multiple cases (Wang et al. 2018. PubMed ID: 30376817; https://www.ncbi.nlm.nih.gov/clinvar/variation/158886/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MEF2C are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene. | Wang J | Molecular genetics & genomic medicine | 2019 | PMID: 31512412 |
| Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation. | Wang J | BMC medical genetics | 2018 | PMID: 30376817 |
| Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. | Zweier M | Human mutation | 2010 | PMID: 20513142 |
Text-mined citations for rs587783747 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.