X-154031430-C-T

Position:

• chrX-154031430-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS2 PM5_Strong PS4 PM2_Supporting PM1 PS3_Supporting PP4 PP3

This summary comes from the ClinGen Evidence Repository: The p.Arg133His variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 4 individuals with classic or atypical Rett syndrome (PMID 30569584, 17089071, 30945278) (PS2_very strong, PP4). The p.Arg133His variant has been observed in at least 3 other individuals with classic or atypical Rett syndrome (PMID 16473305, RettBASE) (PS4). Four additional pathogenic missense variants (p.Arg133Cys, p.Arg133Leu, p.Arg133Pro, p.Arg133Gly) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23421866, 11738879, 26418480, 16473305, 22368975, 10854091, 11960578, 12180070, Invitae - internal database) (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg133His variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM5_strong, PS3_supporting, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274538/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.50

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.434G>A	p.Arg145His	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.398G>A	p.Arg133His	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.434G>A	p.Arg145His	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.398G>A	p.Arg133His	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 08, 2024	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: 16225173, 17089071, 30569584). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).(PMID: 17089071, 16473305, 19133691, 16225173, 30569584,ClinVar Variation ID: 143559). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Arg133His variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 4 individuals with classic or atypical Rett syndrome (PMID 30569584, 17089071, 30945278) (PS2_very strong, PP4). The p.Arg133His variant has been observed in at least 3 other individuals with classic or atypical Rett syndrome (PMID 16473305, RettBASE) (PS4). Four additional pathogenic missense variants (p.Arg133Cys, p.Arg133Leu, p.Arg133Pro, p.Arg133Gly) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23421866, 11738879, 26418480, 16473305, 22368975, 10854091, 11960578, 12180070, Invitae - internal database) (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg133His variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM5_strong, PS3_supporting, PM2_supporting, PP3, PP4). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg133 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11738879, 16473305, 22368975, 23421866, 26418480). 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) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143559). This missense change has been observed in individual(s) with MECP2-related conditions (PMID: 30569584). 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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 133 of the MECP2 protein (p.Arg133His). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2023

Published functional studies demonstrate this variant results in a lower binding affinity of MeCP2 to methylated DNA and decreased ability of MeCP2 to cluster heterochromatin (Agarwal et al., 2011; Yang et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17089071, 11005791, 11402105, 11706982, 12180070, 21831886, 12843318, 16473305, 29655203, 30945278, 27546046, 30569584, 31785789, 32472557, 33504798, 35873028, 34271245, 27356039) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;T;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	D;D;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Benign	0.063	T;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.97
MutPred		0.98		Gain of ubiquitination at K135 (P = 0.0354);.;Gain of ubiquitination at K135 (P = 0.0354);.;Gain of ubiquitination at K135 (P = 0.0354);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs61748389; hg19: chrX-153296881; COSMIC: COSV57652410; COSMIC: COSV57652410;