rs61748391

Positions:

• chrX-154031425-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PP4 PM2_Supporting PS4 PM1 PS3_Supporting PM6

This summary comes from the ClinGen Evidence Repository: The p.Lys135Glu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 22182064) (PM6). The p.Lys135Glu variant has been observed in at least 6 other individuals with Rett syndrome (PMID 11241840, 22982301, 18842453, 16473305, 17387578) (PS4 and PP4). The p.Lys135Glu variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Lys135Glu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). In summary, the p.Lys135Glu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PS3_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270401/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 5.78

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 12 ACMG points.

• 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.
• PM6: 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.439A>G	p.Lys147Glu	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.403A>G	p.Lys135Glu	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.439A>G	p.Lys147Glu	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.403A>G	p.Lys135Glu	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 2.0, 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). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1).This variant is absent from gnomAD (PM2_Supporting).This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6).Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jul 13, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 05, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Lys135Glu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 22182064) (PM6). The p.Lys135Glu variant has been observed in at least 6 other individuals with Rett syndrome (PMID 11241840, 22982301, 18842453, 16473305, 17387578) (PS4 and PP4). The p.Lys135Glu variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Lys135Glu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). In summary, the p.Lys135Glu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PS3_supporting, PP3, PP4). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2023

This missense change has been observed in individuals with Rett syndrome (PMID: 22106023; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 135 of the MECP2 protein (p.Lys135Glu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys135 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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: 143564). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2018

The p.K135E variant (also known as c.403A>G), located in coding exon 3 of the MECP2 gene, results from an A to G substitution at nucleotide position 403. The lysine at codon 135 is replaced by glutamic acid, an amino acid with similar properties. This variant has been observed in various cohorts of females with a clinical diagnosis of Rett syndrome (Laccone F et al. Hum. Mutat., 2001 Mar;17:183-90; Milunsky JM et al. Genet. Test., 2001;5:321-5; Kammoun F et al. J. Med. Genet., 2004 Jun;41:e85; Zahorakova D et al. J. Hum. Genet., 2007 Feb;52:342-8; Lim F et al. Am. J. Med. Genet. A, 2012 Jan;158A:1-9). Furthermore, one functional study using mouse myoblasts demonstrated that this variant significantly decreased chromocenter clustering compared to WT, indicating a reduction in the ability of this variant to bind heterochromatin (Agarwal N et al. Hum. Mol. Genet., 2011 Nov;20:4187-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2021

Functional characterization has shown that the K135E variant impairs the function of the methyl CpG binding domain and weakens the ability of the MECP2 protein to repress transcription (Agarwal et al., 2011; Kudo et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 21831886, 12843318, 31629770, 31356990, 32722525, 24453408, 12180070, 16473305, 27535533, 15173251, 17387578, 11960578, 22106023, 11241840) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	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	0.82	D
PROVEAN	Uncertain	-3.5	D;D;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Benign	0.57	T;T;D;D;.;D;D
Polyphen		0.97	D;D;.;.;.;.;.
Vest4		0.95
MutPred		0.90		Loss of MoRF binding (P = 0.036);.;Loss of MoRF binding (P = 0.036);.;Loss of MoRF binding (P = 0.036);.;.;
MVP		1.0
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61748391; hg19: chrX-153296876;