VCV000143475.11 - ClinVar

NM_001110792.2(MECP2):c.1466G>C (p.Ser489Thr)

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

3 conditions

Reviewed by expert panel

Uncertain significance

Dec 2021 by ClinGen Rett a… FDA Recognized Database

for Rett syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001110792.2(MECP2):c.1466G>C (p.Ser489Thr)

Variation ID: 143475 Accession: VCV000143475.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154030398 (GRCh38) [ NCBI UCSC ] X: 153295849 (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	Apr 22, 2015	Apr 6, 2024	Dec 13, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110792.2:c.1466G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001104262.1:p.Ser489Thr	missense
NM_004992.4:c.1430G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004983.1:p.Ser477Thr	missense
NM_001316337.2:c.1151G>C	NP_001303266.1:p.Ser384Thr	missense
NM_001369391.2:c.1151G>C	NP_001356320.1:p.Ser384Thr	missense
NM_001369392.2:c.1151G>C	NP_001356321.1:p.Ser384Thr	missense
NM_001369393.2:c.1151G>C	NP_001356322.1:p.Ser384Thr	missense
NM_001369394.2:c.1151G>C	NP_001356323.1:p.Ser384Thr	missense
NM_001386137.1:c.761G>C	NP_001373066.1:p.Ser254Thr	missense
NM_001386138.1:c.761G>C	NP_001373067.1:p.Ser254Thr	missense
NM_001386139.1:c.761G>C	NP_001373068.1:p.Ser254Thr	missense
NC_000023.11:g.154030398C>G
NC_000023.10:g.153295849C>G
NG_007107.3:g.111706G>C
LRG_764:g.111706G>C
LRG_764t1:c.1466G>C	LRG_764p1:p.Ser489Thr
LRG_764t2:c.1430G>C	LRG_764p2:p.Ser477Thr
AJ132917.1:c.1430G>C

... more HGVS ... less HGVS

Protein change

S477T, S489T, S384T, S254T

Other names

NM_001110792.2(MECP2):c.1466G>C
p.Ser489Thr

Canonical SPDI

NC_000023.11:154030397:C:G

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.

Links

ClinGen: CA170245 dbSNP: rs267608328 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.
MECP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1901	2229

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.
not specified	Benign (1)	no assertion criteria provided	Nov 1, 2007	RCV000133005.3
Severe neonatal-onset encephalopathy with microcephaly	Benign (1)	criteria provided, single submitter	Dec 6, 2022	RCV001206116.8
Rett syndrome	Uncertain significance (2)	reviewed by expert panel	Dec 13, 2021	RCV001800448.5

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 (Dec 13, 2021)	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2) Method: curation	Rett syndrome (X-linked inheritance) Affected status: unknown Allele origin: germline	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel FDA Recognized Database Accession: SCV002047373.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/32d53fd8-0652-4c83-ba6a-b7a791fb3b20 Comment: The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID 12655490)(BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a … (more) The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID 12655490)(BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The p.Ser477Thr variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Ser477Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, PM2_supporting). (less)
Benign (Dec 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Severe neonatal-onset encephalopathy with microcephaly Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001377408.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024
Uncertain significance (Mar 14, 2024)	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022)) Method: curation	Rett syndrome (X-linked inheritance) Affected status: unknown Allele origin: germline	Centre for Population Genomics, CPG Accession: SCV004809009.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1cb2a32f-0065-4a42-84e5-aba6af89bea3 Comment: This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert … (more) This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).PMID: 12655490 This variant is absent from gnomAD (PM2_Supporting). (less)
Benign (Nov 01, 2007)	no assertion criteria provided Method: curation	Not specified Affected status: not provided Allele origin: unknown	RettBASE Accession: SCV000187992.2 First in ClinVar: Aug 17, 2014 Last updated: Apr 22, 2015	Publications: PubMed (1) PubMed: 17383248 Observation 1: Number of individuals with the variant: 1 Family history: No Sex: male Tissue: blood Comment on evidence: Not Rett synd. - Unaffected family member Observation 2: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Not Rett synd. - Unaffected family member Observation 3: Number of individuals with the variant: 1 Tissue: blood Comment on evidence: Not Rett synd. - sporadic mental retardation

Comment:

The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID 12655490)(BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The p.Ser477Thr variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Ser477Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, PM2_supporting).

Comment:

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).PMID: 12655490 This variant is absent from gnomAD (PM2_Supporting).

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
Mutation screening of the MECP2 gene in a large cohort of 613 fragile-X negative patients with mental retardation.	Lesca G	European journal of medical genetics	2007	PMID: 17383248
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1cb2a32f-0065-4a42-84e5-aba6af89bea3	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/32d53fd8-0652-4c83-ba6a-b7a791fb3b20	-	-	-	-

Text-mined citations for rs267608328 ...

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_001110792.2(MECP2):c.1466G>C (p.Ser489Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608328 ...