VCV000438583.9 - ClinVar

NM_002397.5(MEF2C):c.860C>T (p.Ser287Leu)

Germline

Classification

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.

(2)

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.

Uncertain significance

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.860C>T (p.Ser287Leu)

Variation ID: 438583 Accession: VCV000438583.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q14.3 5: 88729322 (GRCh38) [ NCBI UCSC ] 5: 88025139 (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	Jun 2, 2018	Feb 20, 2024	Oct 30, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_002397.5:c.860C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002388.2:p.Ser287Leu	missense
NM_001131005.2:c.830C>T	NP_001124477.1:p.Ser277Leu	missense
NM_001193347.1:c.890C>T	NP_001180276.1:p.Ser297Leu	missense
NM_001193348.1:c.692C>T	NP_001180277.1:p.Ser231Leu	missense
NM_001193349.3:c.716C>T	NP_001180278.1:p.Ser239Leu	missense
NM_001193350.2:c.860C>T	NP_001180279.1:p.Ser287Leu	missense
NM_001308002.3:c.836C>T	NP_001294931.1:p.Ser279Leu	missense
NM_001363581.2:c.860C>T	NP_001350510.1:p.Ser287Leu	missense
NM_001364329.2:c.860C>T	NP_001351258.1:p.Ser287Leu	missense
NM_001364330.2:c.860C>T	NP_001351259.1:p.Ser287Leu	missense
NM_001364331.2:c.860C>T	NP_001351260.1:p.Ser287Leu	missense
NM_001364332.2:c.716C>T	NP_001351261.1:p.Ser239Leu	missense
NM_001364333.2:c.836C>T	NP_001351262.1:p.Ser279Leu	missense
NM_001364334.2:c.860C>T	NP_001351263.1:p.Ser287Leu	missense
NM_001364335.2:c.860C>T	NP_001351264.1:p.Ser287Leu	missense
NM_001364336.2:c.860C>T	NP_001351265.1:p.Ser287Leu	missense
NM_001364337.2:c.860C>T	NP_001351266.1:p.Ser287Leu	missense
NM_001364338.2:c.890C>T	NP_001351267.1:p.Ser297Leu	missense
NM_001364339.2:c.836C>T	NP_001351268.1:p.Ser279Leu	missense
NM_001364340.2:c.836C>T	NP_001351269.1:p.Ser279Leu	missense
NM_001364341.2:c.836C>T	NP_001351270.1:p.Ser279Leu	missense
NM_001364342.2:c.836C>T	NP_001351271.1:p.Ser279Leu	missense
NM_001364343.2:c.830C>T	NP_001351272.1:p.Ser277Leu	missense
NM_001364344.2:c.716C>T	NP_001351273.1:p.Ser239Leu	missense
NM_001364345.2:c.860C>T	NP_001351274.1:p.Ser287Leu	missense
NM_001364346.2:c.860C>T	NP_001351275.1:p.Ser287Leu	missense
NM_001364347.2:c.860C>T	NP_001351276.1:p.Ser287Leu	missense
NM_001364348.2:c.836C>T	NP_001351277.1:p.Ser279Leu	missense
NM_001364349.2:c.836C>T	NP_001351278.1:p.Ser279Leu	missense
NM_001364350.2:c.836C>T	NP_001351279.1:p.Ser279Leu	missense
NM_001364352.2:c.830C>T	NP_001351281.1:p.Ser277Leu	missense
NM_001364353.2:c.482C>T	NP_001351282.1:p.Ser161Leu	missense
NM_001364354.2:c.716C>T	NP_001351283.1:p.Ser239Leu	missense
NM_001364355.2:c.716C>T	NP_001351284.1:p.Ser239Leu	missense
NM_001364356.2:c.482C>T	NP_001351285.1:p.Ser161Leu	missense
NM_001364357.2:c.410C>T	NP_001351286.1:p.Ser137Leu	missense
NC_000005.10:g.88729322G>A
NC_000005.9:g.88025139G>A
NG_023427.1:g.179784C>T

... more HGVS ... less HGVS

Protein change

S277L, S287L, S231L, S279L, S297L, S137L, S161L, S239L

Other names

Canonical SPDI

NC_000005.10:88729321:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA3337223 dbSNP: rs777826971 VarSome

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
Gene	OMIM	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.
Intellectual disability, autosomal dominant 20	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 30, 2019	RCV000656084.9

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.
Uncertain significance (Sep 01, 2017)	criteria provided, single submitter (Wiszniewski et al. (Eur J Hum Genet. 2018)) Method: research	Intellectual disability, autosomal dominant 20 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000598582.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018	Publications: PubMed (1) PubMed: 29706646 Comment: this variant was indentified in an individual with malformations of cortical development Number of individuals with the variant: 1 Clinical Features: Abnormality of neuronal migration (present) Method: WES
Uncertain significance (Oct 30, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Intellectual disability, autosomal dominant 20 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001398578.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 29706646 Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in an individual with polymicrogyria, microcephaly, and tetraparesis (PMID: 29706646). It is also known as c.890C>T (p.Ser297Leu) in the literature. ClinVar contains an entry for this variant (Variation ID: 438583). This variant is present in population databases (rs777826971, ExAC 0.002%). This sequence change replaces serine with leucine at codon 287 of the MEF2C protein (p.Ser287Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. (less)

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in an individual with polymicrogyria, microcephaly, and tetraparesis (PMID: 29706646). It is also known as c.890C>T (p.Ser297Leu) in the literature. ClinVar contains an entry for this variant (Variation ID: 438583). This variant is present in population databases (rs777826971, ExAC 0.002%). This sequence change replaces serine with leucine at codon 287 of the MEF2C protein (p.Ser287Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive genomic analysis of patients with disorders of cerebral cortical development.	Wiszniewski W	European journal of human genetics : EJHG	2018	PMID: 29706646

Text-mined citations for rs777826971 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002397.5(MEF2C):c.860C>T (p.Ser287Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777826971 ...