X-154031154-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001110792.2(MECP2):c.710C>G(p.Pro237Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P237T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.89

Publications

24 publications found

Variant links:

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

chromosome Xq28 duplication syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
Rett syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
severe neonatal-onset encephalopathy with microcephaly
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
syndromic X-linked intellectual disability Lubs type
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability-psychosis-macroorchidism syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154031155-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant X-154031154-G-C is Pathogenic according to our data. Variant chrX-154031154-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 143653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.710C>G	p.Pro237Arg	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.674C>G	p.Pro225Arg	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.710C>G	p.Pro237Arg	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.674C>G	p.Pro225Arg	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome

Pathogenic:5

May 18, 2012

RettBASE

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 08, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.89 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143653 /PMID: 10767337). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 10767337). Different missense changes at the same codon (p.Pro237Leu, p.Pro237Thr) have been reported to be associated with MECP2-related disorder (ClinVar ID: VCV000011841, VCV000143652 /PMID: 12615169, 32469098). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 22, 2024

Centre for Population Genomics, CPG

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

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: This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong).(PMID: 17089071, 10767337). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 31427717, 17407838, 17387578, 17089071, 16473305, 19133691, 18842453, 10767337, 11245712). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting).

Jun 14, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS3, PS4, PM2, PP3

not provided

Pathogenic:3

Jul 14, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 20, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 29718204); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29782864, 22139899, 22190343, 34800434, 10767337, 12075485, 12111643, 16473305, 16690727, 17142618, 15675358, 12746405, 11214906, 12655490, 21954873, 18842453, 12180070, 11524741, 19133691, 18056689, 15880509, 26469135, 11245712, 26984561, 21160487, 17387578, 10805343, 17089071, 10854091, 33880059, 32472557, 32005694, 33994118, 33084218, 35606502, 34926809, 35982159, 31440721, 21831886, 29718204)

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Severe neonatal-onset encephalopathy with microcephaly

Pathogenic:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12615169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143653). This missense change has been observed in individual(s) with either classic or atypical Rett syndrome (PMID: 10767337, 10854091, 11524741, 12075485, 12111643, 16473305, 16690727, 17142618). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the MECP2 protein (p.Pro225Arg).

Seizure;C0425492:Irregular respiration;C1836830:Developmental regression;C1837397:Severe global developmental delay;C1854882:Absent speech

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability

Pathogenic:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MECP2-related disorder

Pathogenic:1

Aug 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MECP2 c.674C>G variant is predicted to result in the amino acid substitution p.Pro225Arg. This variant was reported in multiple individuals with Rett syndrome, epilepsy or intellectual disability and has been described as a recurrent causative variant documented as de novo in at least one patient (Cheadle et al. 2000. PubMed ID: 10767337; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S2, Dong et al. 2020. PubMed ID: 32005694; Table S1, Wen et al. 2020. PubMed ID: 32472557). In vitro functional studies found this variant interferes with protein function through decreased stability or conformational changes (Guy et al. 2018. PubMed ID: 29718204). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;T;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

D;D;.;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

D;D;.;.

Sift4G

Benign

0.12

T;D;.;D

Vest4

0.89

ClinPred

0.96

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.96

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over