rs28934908

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001110792.2(MECP2):c.455C>T(p.Ala152Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32O:1

Conservation

PhyloP100: 9.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.965

PP5

Variant X-154031409-G-A is Pathogenic according to our data. Variant chrX-154031409-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031409-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154031409-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.455C>T	p.Ala152Val	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.419C>T	p.Ala140Val	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.455C>T	p.Ala152Val	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.419C>T	p.Ala140Val	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097434

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362798

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:32Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Jul 17, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30542205, 33144682, 32581362, 32371413, 12325019, 27465203, 24328834, 25473036, 29431277, 30536762, 31273722, 11885030, 11007980, 26418480, 26350204, 11805248, 27929079, 12843318, 21831886) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 26, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2023

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2018

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Pathogenic:6

Nov 04, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability display X-linked recessive inheritance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated methyl-CpG binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in multiple individuals with non-classic Rett syndrome or moderate-severe intellectual disability with movement disorder (ClinVar, GeneReviews, DECIPHER). (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 05, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM5_STR,PS2_MOD,PM2_SUP,PP2,PP3 -

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 11309367, 30536762, 11007980, 11885030, ClinVar Variation ID: 11823) Co-segregation with disease in multiple affected family members (3-4 informative meiosis) informative meiosis (PP1_Moderate). (PMID: 11007980, 11885030) 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). -

Sep 22, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome

Pathogenic:3Other:1

Apr 26, 2016

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

TIDEX, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Hemizygote Missense variant c.419C>T in Exon 4 of the MECP2 gene that results in the amino acid substitution p.Ala140Val was identified. The observed variant has a minor allele frequency of 0.0 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variation ID: 11823). The variant has been previously reported by Winnepenninckx B, et al., 2002. Experimental study by Agarwal N, et al., 2011 showed MECP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, and their dysfunction lead to Rett syndrome. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly

Pathogenic:2

Jul 03, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PS3, PM1, PM2, PS4_Moderate, PP1, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_Strong+PS4_Moderate+PM2_Supporting+PP3+PP4+PS3_Moderate -

Syndromic X-linked intellectual disability Lubs type

Pathogenic:2

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MECP2 c.455C>T variant is classified as PATHOGENIC (PS4, PP1_strong, PM2, PP3) The MECP2 c.455C>T variant is a single nucleotide change in exon 3/3 of the MECP2 gene, which is predicted to change the amino acid alanine at position 152 in the protein to valine. This recurrent variant has been reported in multiple individuals with a clinical presentation of X-linked syndromic Intellectual disability or non-classic Rett phenotype (PS4). This variant has been reported in dbSNP (rs28934908) but is absent from population databases (PM2). This variant has been reported to co-segregate with disease in a large number of individuals in multiple families (PMID:11007980, PMID:26350204, PMID:25473036, PMID:27465203, PMID:12325019) (PP1_strong). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has been reported in ClinVar as Pathogenic / Likely Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 11823) and is classified as damaging in the HGMD disease database (CM003325). -

Inborn genetic diseases

Pathogenic:1

Sep 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419C>T (p.A140V) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 419, causing the alanine (A) at amino acid position 140 to be replaced by a valine (V)._x000D_ _x000D_ Based on the available evidence, the MECP2 c.419C>T (p.A140V) alteration is classified as pathogenic for X-linked recessive MECP2-related neurodevelopmental disorder; however, this variant is unlikely to be causative of X-linked dominant typical RTT, atypical RTT, or neonatal severe encephalopathy. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in numerous individuals and families with affected males demonstrating moderate to severe intellectual disability and movement disorders, and carrier females showing mild intellectual disability or who appear to be unaffected (Orrico, 2000; Couvert, 2001; Lambert, 2016). In addition, co-segregation with clinical findings has been described across multiple families (Orrico, 2000; Winnepenninckx, 2002; Lambert, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Atypical behavior

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Intellectual disability

Pathogenic:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MECP2-related disorder

Pathogenic:1

Jun 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MECP2 c.419C>T variant is predicted to result in the amino acid substitution p.Ala140Val. This variant has been reported in several patients to be causative for X-linked intellectual disability with variable neurobehavioral and dysmorphic features (see for example, Orrico et al. 2000. PubMed ID: 11007980; Sheik et al. 2016. PubMed ID: 27929079; Lambert et al. 2016. PubMed ID: 27465203; Venkateswaran et al. 2014. PubMed ID: 24328834). In vitro functional studies demonstrate this variant affects MECP2 function (Nan et al. 2007. PubMed ID: 17296936; Sheikh et al. 2016. PubMed ID: 27929079) and a mouse model demonstrates this variant disrupts neuronal signaling. This variant has not been reported in a large population database, indicating this variant is rare. Taken together, this variant is interpreted as pathogenic. -

Severe neonatal-onset encephalopathy with microcephaly

Pathogenic:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the MECP2 protein (p.Ala140Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurodevelopmental disorders (PMID: 11007980, 12325019, 25473036, 26350204, 27465203). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11823). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 does not substantially affect MECP2 function (PMID: 12843318, 21831886, 26418480). For these reasons, this variant has been classified as Pathogenic. -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome

Pathogenic:1

Jul 12, 2024

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder

Pathogenic:1

Apr 03, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism, susceptibility to, X-linked 3

Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. -

Micrognathia;C0395837:Stenosis of the external auditory canal;C0423110:Downslanted palpebral fissures;C1384666:Hearing impairment;C1854301:Motor delay;C1859778:Postnatal growth retardation;C3714756:Intellectual disability;C4551563:Microcephaly

Pathogenic:1

Sep 10, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;T;D;D;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

L;.;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.0

N;N;.;.;.;.;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.015

D;D;.;.;.;.;.

Sift4G

Uncertain

0.042

D;D;D;D;.;D;D

Polyphen

1.0

D;D;.;.;.;.;.

Vest4

0.64

MutPred

0.83

Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);.;.;

MVP

1.0

ClinPred

0.96

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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