NM_001110792.2:c.437C>G

Variant names:

• chrX-154031427-G-C
• rs61748390
• NM_001110792.2:c.437C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001110792.2(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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.437C>G	p.Ser146Cys	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.401C>G	p.Ser134Cys	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.437C>G	p.Ser146Cys	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.401C>G	p.Ser134Cys	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:11

Jun 11, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 01, 2011

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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Mar 08, 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: 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). -

Jul 07, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 11, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 34837432). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.99 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143562 /PMID: 10767337). Different missense changes at the same codon (p.Ser146Phe, p.Ser146Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143563 /PMID: 15526954, 15737703). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 09, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP,PP3 -

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Jul 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.;.;.;.
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;