VCV000036492.21 - ClinVar

NM_001110792.2(MECP2):c.1477G>A (p.Val493Met)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

5 conditions

Reviewed by expert panel

Likely benign

Feb 2022 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.1477G>A (p.Val493Met)

Variation ID: 36492 Accession: VCV000036492.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154030387 (GRCh38) [ NCBI UCSC ] X: 153295838 (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 24, 2015	Oct 8, 2024	Feb 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110792.2:c.1477G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001104262.1:p.Val493Met	missense
NM_004992.4:c.1441G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004983.1:p.Val481Met	missense
NM_001316337.2:c.1162G>A	NP_001303266.1:p.Val388Met	missense
NM_001369391.2:c.1162G>A	NP_001356320.1:p.Val388Met	missense
NM_001369392.2:c.1162G>A	NP_001356321.1:p.Val388Met	missense
NM_001369393.2:c.1162G>A	NP_001356322.1:p.Val388Met	missense
NM_001369394.2:c.1162G>A	NP_001356323.1:p.Val388Met	missense
NM_001386137.1:c.772G>A	NP_001373066.1:p.Val258Met	missense
NM_001386138.1:c.772G>A	NP_001373067.1:p.Val258Met	missense
NM_001386139.1:c.772G>A	NP_001373068.1:p.Val258Met	missense
NC_000023.11:g.154030387C>T
NC_000023.10:g.153295838C>T
NG_007107.3:g.111717G>A
LRG_764:g.111717G>A
LRG_764t1:c.1477G>A	LRG_764p1:p.Val493Met
LRG_764t2:c.1441G>A	LRG_764p2:p.Val481Met
AJ132917.1:c.1441G>A

... more HGVS ... less HGVS

Protein change

V481M, V493M, V388M, V258M

Other names

p.V481M:GTG>ATG
NM_001110792.2(MECP2):c.1477G>A
p.Val493Met

Canonical SPDI

NC_000023.11:154030386:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA208886 dbSNP: rs193922678 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.
Rett syndrome	Likely benign (4)	reviewed by expert panel	Feb 18, 2022	RCV000030164.7
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 25, 2013	RCV000194612.11
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 24, 2020	RCV000724867.10
Severe neonatal-onset encephalopathy with microcephaly	Benign (1)	criteria provided, single submitter	Oct 31, 2023	RCV001057144.7
MECP2-related disorder	Likely benign (1)	no assertion criteria provided	Mar 12, 2024	RCV004734534.1

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.
Likely benign (Feb 18, 2022)	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: SCV002540691.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/15f6f99d-7268-4eee-9cb6-ad481b36ae07 Comment: The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present … (more) The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). (less)
Uncertain significance (Feb 25, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247954.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Uncertain significance (Jun 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332088.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 Number of individuals with the variant: 2 Sex: mixed
Likely benign (Aug 24, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000191003.13 First in ClinVar: Nov 01, 2014 Last updated: Jul 24, 2021	Comment: Reported as a variant of uncertain significance in a female with history of developmental regression and meeting clinical criteria for Rett syndrome (Zvereff et al., … (more) Reported as a variant of uncertain significance in a female with history of developmental regression and meeting clinical criteria for Rett syndrome (Zvereff et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 22277191) (less)
Likely benign (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: SCV004808735.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5de6a02d-838a-4f42-9f9e-b09dfb896239 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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Variant is found in an individual with an alternate molecular basis of disease (BP5). (less)
Benign (Oct 31, 2023)	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: SCV001221621.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024
Uncertain significance (Mar 13, 2015)	no assertion criteria provided Method: clinical testing	Rett's disorder Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052822.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2015	Comment: The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The Valine at position 493 is highly conserved … (more) The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The Valine at position 493 is highly conserved in evolution, though computational tools do not provide strong support for or against an impact to the protein. The variant has been reported previously in two female patients with Rett syndrome (Fong et al 2009/MECP2 database and Zvereff et al 2012), however family history was not provided. This variant is more likely pathogenic but additional studies are needed to fully assess its clinical significance. (less)
Uncertain significance (Sep 27, 2012)	no assertion criteria provided Method: curation	Rett syndrome Affected status: yes Allele origin: unknown	RettBASE Accession: SCV000187995.2 First in ClinVar: Aug 15, 2014 Last updated: Apr 24, 2015	Publications: PubMed (1) PubMed: 22277191 Observation 1: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 2: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical
Likely benign (Mar 12, 2024)	no assertion criteria provided Method: clinical testing	MECP2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005363751.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).

Comment:

Reported as a variant of uncertain significance in a female with history of developmental regression and meeting clinical criteria for Rett syndrome (Zvereff et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 22277191)

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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Variant is found in an individual with an alternate molecular basis of disease (BP5).

Comment:

The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The Valine at position 493 is highly conserved in evolution, though computational tools do not provide strong support for or against an impact to the protein. The variant has been reported previously in two female patients with Rett syndrome (Fong et al 2009/MECP2 database and Zvereff et al 2012), however family history was not provided. This variant is more likely pathogenic but additional studies are needed to fully assess its clinical significance.

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
Molecular diagnostic dilemmas in Rett syndrome.	Zvereff V	Brain & development	2012	PMID: 22277191
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/15f6f99d-7268-4eee-9cb6-ad481b36ae07	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5de6a02d-838a-4f42-9f9e-b09dfb896239	-	-	-	-

Text-mined citations for rs193922678 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001110792.2(MECP2):c.1477G>A (p.Val493Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs193922678 ...