rs28934908

chrX-154031409-G-AchrX-154031409-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. A152A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• 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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001110792.2
• 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/exons	MANE	UniProt
MECP2	NM_001110792.2	c.455C>T	p.Ala152Val	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.419C>T	p.Ala140Val	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.455C>T	p.Ala152Val	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.419C>T	p.Ala140Val	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097434 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 1 AN XY: 362798

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.: 23

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	Dec 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 05, 2023	Criteria applied: PS4,PM5_STR,PS2_MOD,PM2_SUP,PP2,PP3 -
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: 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Nov 04, 2022	- -

Rett syndrome Pathogenic:3 Other:1

Likely pathogenic, no assertion criteria provided	research	RettBASE	Apr 26, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

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). 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. 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. -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 23, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

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

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 03, 2020

- -

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:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 03, 2018

[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]. -

Autism, susceptibility to, X-linked 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 10, 2015

- -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;T;D;D;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
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	D
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

Other links and lift over

dbSNP: rs28934908; hg19: chrX-153296860; COSMIC: COSV57653043; COSMIC: COSV57653043;