VCV000156670.40 - ClinVar

NM_001110792.2(MECP2):c.737C>G (p.Ala246Gly)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

5 conditions

Reviewed by expert panel

Benign

Dec 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.737C>G (p.Ala246Gly)

Variation ID: 156670 Accession: VCV000156670.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154031127 (GRCh38) [ NCBI UCSC ] X: 153296578 (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	Dec 6, 2016	Oct 20, 2024	Dec 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110792.2:c.737C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001104262.1:p.Ala246Gly	missense
NM_004992.4:c.701C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004983.1:p.Ala234Gly	missense
NM_001316337.2:c.422C>G	NP_001303266.1:p.Ala141Gly	missense
NM_001369391.2:c.422C>G	NP_001356320.1:p.Ala141Gly	missense
NM_001369392.2:c.422C>G	NP_001356321.1:p.Ala141Gly	missense
NM_001369393.2:c.422C>G	NP_001356322.1:p.Ala141Gly	missense
NM_001369394.2:c.422C>G	NP_001356323.1:p.Ala141Gly	missense
NM_001386137.1:c.32C>G	NP_001373066.1:p.Ala11Gly	missense
NM_001386138.1:c.32C>G	NP_001373067.1:p.Ala11Gly	missense
NM_001386139.1:c.32C>G	NP_001373068.1:p.Ala11Gly	missense
NC_000023.11:g.154031127G>C
NC_000023.10:g.153296578G>C
NG_007107.3:g.110977C>G
LRG_764:g.110977C>G
LRG_764t1:c.737C>G	LRG_764p1:p.Ala246Gly
LRG_764t2:c.701C>G	LRG_764p2:p.Ala234Gly

... more HGVS ... less HGVS

Protein change

A234G, A246G, A141G, A11G

Other names

p.A234G:GCT>GGT
NM_001110792.2(MECP2):c.737C>G
p.Ala246Gly

Canonical SPDI

NC_000023.11:154031126:G:C

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) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

Links

ClinGen: CA294719 dbSNP: rs138211345 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	1896	2224

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.
Severe neonatal-onset encephalopathy with microcephaly	Likely benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001079662.9
Rett syndrome	Benign (1)	reviewed by expert panel	Dec 8, 2022	RCV002472365.3
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 1, 2021	RCV000723954.31
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Aug 7, 2017	RCV002362777.3
MECP2-related disorder	Likely benign (1)	no assertion criteria provided	Jan 31, 2022	RCV004544329.2

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.
Benign (Dec 08, 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: SCV002769735.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/21681f8f-ca00-41a5-a493-384733758727 Comment: The allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be … (more) The allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala234Gly variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Ala234Gly variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). (less)
Uncertain significance (May 27, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230248.5 First in ClinVar: Jun 29, 2015 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: 1 Sex: mixed
Likely benign (Dec 21, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000191045.11 First in ClinVar: Nov 02, 2014 Last updated: Mar 04, 2023
Uncertain significance (Sep 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001962673.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely benign (Jan 31, 2024)	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: SCV001002475.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Likely benign (Aug 07, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002666906.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jan 31, 2022)	no assertion criteria provided Method: clinical testing	MECP2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004785321.2 First in ClinVar: Mar 16, 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 allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala234Gly variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Ala234Gly variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2).

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/21681f8f-ca00-41a5-a493-384733758727	-	-	-	-

Text-mined citations for rs138211345 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001110792.2(MECP2):c.737C>G (p.Ala246Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138211345 ...