rs61751444

Positions:

• chrX-154030903-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PS4 PS2 PP4

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 ENST00000453960.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:22 U:3 O:1
• Conservation: PhyloP100: 2.16

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 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/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.961C>T	p.Arg321Trp	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.925C>T	p.Arg309Trp	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.961C>T	p.Arg321Trp	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.925C>T	p.Arg309Trp	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:11 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 22, 2023	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Likely pathogenic, criteria provided, single submitter	case-control	Biochemistry Laboratory of CDMU, Chengde Medical University	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jul 28, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 02, 2023	PS2_Very Strong, PS4, PM2, PP3 -
Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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>=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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 24, 2024	Criteria applied: PS2_VSTR,PS4,PM2_SUP,PM5_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Jun 02, 2020	- -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	Oct 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	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) -

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

Uncertain significance, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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 -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

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

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2015

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 05, 2019

- -

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

Uncertain significance, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

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
MutationTaster	Benign	1.0	D;D
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

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