X-154032282-G-C

Position:

• chrX-154032282-G-C

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.338C>G	p.Pro113Arg	missense_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.302C>G	p.Pro101Arg	missense_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.338C>G	p.Pro113Arg	missense_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.302C>G	p.Pro101Arg	missense_variant	3/4	1	NM_004992.4	P1

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

Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 15, 2011	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Apr 28, 2022	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). -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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: >=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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2021

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. Experimental studies have shown that this missense change affects MECP2 protein function (PMID: 21831886). 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. ClinVar contains an entry for this variant (Variation ID: 143526). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Angelman syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Feb 15, 2011

- -

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;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
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: rs61754453; hg19: chrX-153297733;