VCV000143734.4 - ClinVar

NM_001110792.2(MECP2):c.940C>G (p.Pro314Ala)

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001110792.2(MECP2):c.940C>G (p.Pro314Ala)

Variation ID: 143734 Accession: VCV000143734.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154030924 (GRCh38) [ NCBI UCSC ] X: 153296375 (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	Sep 16, 2024	Jan 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110792.2:c.940C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001104262.1:p.Pro314Ala	missense
NM_004992.4:c.904C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004983.1:p.Pro302Ala	missense
NM_001316337.2:c.625C>G	NP_001303266.1:p.Pro209Ala	missense
NM_001369391.2:c.625C>G	NP_001356320.1:p.Pro209Ala	missense
NM_001369392.2:c.625C>G	NP_001356321.1:p.Pro209Ala	missense
NM_001369393.2:c.625C>G	NP_001356322.1:p.Pro209Ala	missense
NM_001369394.2:c.625C>G	NP_001356323.1:p.Pro209Ala	missense
NM_001386137.1:c.235C>G	NP_001373066.1:p.Pro79Ala	missense
NM_001386138.1:c.235C>G	NP_001373067.1:p.Pro79Ala	missense
NM_001386139.1:c.235C>G	NP_001373068.1:p.Pro79Ala	missense
NC_000023.11:g.154030924G>C
NC_000023.10:g.153296375G>C
NG_007107.3:g.111180C>G
LRG_764:g.111180C>G
LRG_764t1:c.940C>G	LRG_764p1:p.Pro314Ala
LRG_764t2:c.904C>G	LRG_764p2:p.Pro302Ala
	P51608:p.Pro302Ala
AJ132917.1:c.904C>G

... more HGVS ... less HGVS

Protein change

P302A, P314A, P209A, P79A

Other names

NM_001110792.2(MECP2):c.940C>G
p.Pro314Ala

Canonical SPDI

NC_000023.11:154030923: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.

Links

ClinGen: CA270565 UniProtKB: P51608#VAR_018206 dbSNP: rs61751373 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.
Rett syndrome	Pathogenic (2)	criteria provided, single submitter	Jan 10, 2024	RCV000133277.4
X-linked intellectual disability-psychosis-macroorchidism syndrome	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247514.1
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2023	RCV004700458.1

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 (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	X-linked intellectual disability-psychosis-macroorchidism syndrome Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517595.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jan 10, 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: SCV004232262.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/472efc18-6a8a-4526-abb4-4d4b6685333a 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 pathogenic. At least the following criteria are met: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 16473305, 10814718, 11245712, 12075494, 11738883, ClinVar Variation ID:143734) Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 10814718). This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). (less)
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201751.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21831886, 11214906, 10814718, 11245712, 16473305, 11738883, 11005791) (less)
Uncertain significance (Jan 21, 2008)	no assertion criteria provided Method: curation	Rett syndrome Affected status: yes Allele origin: unknown, de novo	RettBASE Accession: SCV000188285.2 First in ClinVar: Aug 17, 2014 Last updated: Apr 24, 2015	Publications: PubMed (4) PubMed: 10814718‚ 11245712‚ 11738883‚ 16473305 Observation 1: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 2: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Classical Observation 3: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - Preserved speech Observation 4: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain

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 pathogenic. At least the following criteria are met: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 16473305, 10814718, 11245712, 12075494, 11738883, ClinVar Variation ID:143734) Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 10814718). This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3).

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21831886, 11214906, 10814718, 11245712, 16473305, 11738883, 11005791)

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
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update.	Philippe C	European journal of medical genetics	2006	PMID: 16473305
Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation.	Giunti L	Brain & development	2001	PMID: 11738883
MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.	Auranen M	Neurology	2001	PMID: 11245712
Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.	Huppke P	Human molecular genetics	2000	PMID: 10814718
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/472efc18-6a8a-4526-abb4-4d4b6685333a	-	-	-	-

Text-mined citations for rs61751373 ...

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.940C>G (p.Pro314Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61751373 ...