chrX-154031427-G-C

Position:

• chrX-154031427-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.437C>G​(p.Ser146Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S146F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.46

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 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000453960.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031427-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143563.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-154031427-G-C is Pathogenic according to our data. Variant chrX-154031427-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031427-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.437C>G	p.Ser146Cys	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.401C>G	p.Ser134Cys	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.437C>G	p.Ser146Cys	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.401C>G	p.Ser134Cys	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/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:10

Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
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: 17089071, 10991688, 11269512) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 17407838, 17387578, 11269512, 17089071, 11738864, 10991688, 10814718, ClinVar Variation ID: 143562) 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	New York Genome Center	Jun 11, 2021	The heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is a known pathogenic variant and has been reported in multiple unrelated individuals affected with Rett syndrome [PMID:10767337; PMID:12661945; PMID:21228398; PMID:26418480; PMID: 31164858]. The variant has been reported as Pathogenic/Likely Pathogenic in ClinVar by multiple independent laboratories [Variation ID: 143562]. The variant is absent from gnomAD(v3) suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools [CADD score = 27.7, REVEL score = 0.988). Functional studies have suggested that the c.401C>G (p.Ser134Cys) variant destabilizes the MBD domain of the MECP2 protein and reduces its ability to bind and cluster heterochromatin [PMID: 26418480; PMID: 21831886]. Based on the available evidence, the heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is reported as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	RettBASE	Nov 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2021	Variant summary: MECP2 c.401C>G (p.Ser134Cys) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181626 control chromosomes (gnomAD). c.401C>G has been reported in the literature in multiple individuals affected with Rett Syndrome, in some cases as a de novo mutation (example: Chapleau_2013, Li_2007, Neul_2008, Petel-Galil_2006, Roende_2011, Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant has been reported to reduce the ability of the MECP2 protein to bind and cluster heterochromatin and was shown to cause destabilization of the methyl-CpG-binding domain of the protein (example: Agarwal_2011, Kucukkal_2015). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.401C>G;p.(Ser134Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 143562; PMID: 10814718; PMID: 11738864; PMID: 17089071; PMID: 12655490; PMID: 21160487; PMID: 11738883; PMID: 18337588) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (MBD) - PM1. This variant is not present in population databases (rs61748390- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 143563) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 10767337; 23696494; 22182064) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 09, 2023	Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP,PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2024	Published functional studies suggest reduced ability of the MECP2 protein to bind and cluster heterochromatin (PMID: 21831886, 26418480); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12843318, 10767337, 11269512, 24508304, 21228398, 26418480, 12661945, 28477699, 29428602, 31164858, 32472557, 35982159, 31440721, 21831886) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MECP2 protein (p.Ser134Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 10814718, 11738864, 11738883, 12655490, 17089071, 18337588, 21160487, 22182064, 23696494). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143562). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 26418480). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2021

The c.401C>G (p.S134C) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to G substitution at nucleotide position 401, causing the serine (S) at amino acid position 134 to be replaced by a cysteine (C). This mutation has been detected in individuals with typical and atypical Rett syndrome, including several de novo occurrences (Li, 2007; Liebhaber, 2003; Vacca, 2001; Cheadle, 2000; Huppke, 2000). Based on internal structural analysis, this alteration impairs a non-specific protein-DNA interaction that is important for function (Ho, 2008). In addition, in one functional study using mouse myoblasts, authors show that this mutation significantly decreased chromocenter clustering compared to wildtype indicating a reduction in the ability of this variant to bind heterochromatin (Agarwal, 2011). Based on the available evidence, this alteration is classified as pathogenic. -

MECP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The MECP2 c.401C>G variant is predicted to result in the amino acid substitution p.Ser134Cys. This variant has been reported to be causative for Rett Syndrome in multiple unrelated patients (Weaving et al. 2003. PubMed ID: 12655490; Li et al. 2007. PubMed ID: 17089071; Hadzsiev et al. 2011. PubMed ID: 21160487), including at least three patients in which the variant occurred de novo (Cheadle et al. 2000. PubMed ID: 10767337; Zhang et al. 2012. PubMed ID: 22182064; Chapleau et al. 2013. PubMed ID: 23696494). Functional studies have demonstrated this variant impacts the ability of MECP2 to interact with heterochromatin (Kucukkal et al. 2015. PubMed ID: 26418480). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;.;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D;D;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.95		Gain of methylation at K135 (P = 0.0153);.;Gain of methylation at K135 (P = 0.0153);.;Gain of methylation at K135 (P = 0.0153);.;.;
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		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61748390; hg19: chrX-153296878;