rs61751444

Variant names:

• chrX-154030903-G-A
• rs61751444
• NM_001110792.2:c.961C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS2 PP4 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199325/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:23 U:3 O:1
• Conservation: PhyloP100: 2.16
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.961C>T	p.Arg321Trp	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.925C>T	p.Arg309Trp	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.961C>T	p.Arg321Trp	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.925C>T	p.Arg309Trp	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:12 Uncertain:1 Other:1

Jun 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4). -

Apr 12, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2024

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,PM2_SUP,PM5_SUP,PP3 -

Jun 02, 2020

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 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>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). (PMID: 31178897, 26936630) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 26936630, 21178819, 30536762, 21160487, 28089766, 37361459, 31178897 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

Jan 03, 2025

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinGen MECP2 VCEP: PS2_VeryStrong, PS4, PM2_Supporting, PP4 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 05, 2013

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

-

Biochemistry Laboratory of CDMU, Chengde Medical University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Mar 02, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_Very Strong, PS4, PM2, PP3 -

not provided Pathogenic:5

Oct 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227) -

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Oct 28, 2019

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:2 Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly -

Dec 05, 2013

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

-

Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been classified as Pathogenic. -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Mar 14, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Dec 14, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1

Apr 05, 2019

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 05, 2013

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.61	D
PhyloP100		2.2
Sift4G	Uncertain	0.057	T
Vest4		0.48
MVP		0.92
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61751444; hg19: chrX-153296354; COSMIC: COSV57656812; COSMIC: COSV57656812;