X-154032282-G-C

Variant names:

• chrX-154032282-G-C
• rs61754453
• NM_001110792.2:c.338C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PM5_Strong PS4

This summary comes from the ClinGen Evidence Repository: The p.Pro101Arg variant in MECP2 (NM_004992.4) has been observed in 4 other individuals with Rett Syndrome (PMID 10991689, RettBASE proband ID: 4426, 6597, 6598) and another individual with Angelman syndrome-like phenotype (PMID 11283202) (PS4). Multiple pathogenic missense variants (p.Pro101His, p.Pro101Leu, p.Pro101Thr, p.Pro101Ser) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11269512, RettBASE)(PM5_Strong). The p.Pro101Arg variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary the p.Pro101Arg variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS4, PM5_Strong, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274626/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 25)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 9.47
• Publications: 12 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.338C>G	p.Pro113Arg	missense_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.302C>G	p.Pro101Arg	missense_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.338C>G	p.Pro113Arg	missense_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.302C>G	p.Pro101Arg	missense_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Feb 15, 2011

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 13, 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: >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 10991689, 11283202, 16225173, 31439979, ClinVar Variation ID: 143526 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Pro101Arg variant in MECP2 (NM_004992.4) has been observed in 4 other individuals with Rett Syndrome (PMID 10991689, RettBASE proband ID: 4426, 6597, 6598) and another individual with Angelman syndrome-like phenotype (PMID 11283202) (PS4). Multiple pathogenic missense variants (p.Pro101His, p.Pro101Leu, p.Pro101Thr, p.Pro101Ser) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11269512, RettBASE)(PM5_Strong). The p.Pro101Arg variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary the p.Pro101Arg variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS4, PM5_Strong, PM2_supporting, PP3). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Jul 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 101 of the MECP2 protein (p.Pro101Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This missense change has been observed in individual(s) with clinical features of X-linked dominant Rett syndrome (PMID: 10991689, 11283202, 16225173, 31439979). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143526). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MECP2 protein function (PMID: 21831886). This variant disrupts the p.Pro101 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 21831886). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Angelman syndrome Uncertain:1

Feb 15, 2011

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;T;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.8	D;D;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.92		Gain of MoRF binding (P = 0.0057);.;Gain of MoRF binding (P = 0.0057);.;Gain of MoRF binding (P = 0.0057);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61754453; hg19: chrX-153297733;