chrX-154031260-G-A

Variant names:

• chrX-154031260-G-A
• rs587783137
• NM_001110792.2:c.604C>T

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. BS2 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004992.4:c.568C>T (p.Arg190Cys) variant in MECP2 is observed in at least 2 unaffected individuals (GeneDx internal database, LabCorp Genetics Inc. internal database) (BS2). Quantitative immunofluorescence localization assays have shown that this variant impacts protein function (PMID:29431277) (PS3_Supporting). The highest population frequency in gnomAD v4.1 is 0.00002 in the European (Finnish) population (BS1_Not Met). The p.Arg190Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID:24776741) (PS2 - not met as patient was not described to have features of Rett syndrome). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.626). A missense variant (p.Arg190His) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5- not met). In summary, the p.Arg190Cys variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS3_Supporting) (MECP2 Specifications v3.0; curation approved on 02/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294710/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 4.23
• Publications: 11 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: Uncertain_significance. The variant received -3 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.604C>T	p.Arg202Cys	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.568C>T	p.Arg190Cys	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001386137.1		c.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 6	NP_001373066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.604C>T	p.Arg202Cys	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.568C>T	p.Arg190Cys	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.568C>T	p.Arg190Cys	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183282 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098224 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 2 AN XY: 363580

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000712 AC: 6 AN: 842117

Other (OTH) AF: 0.0000217 AC: 1 AN: 46097

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000789 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:2

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory in a 7-year-old female with global delays, regression, autism, hypotonia, epilepsy, aggressive behavior. Mom did not carry the variant, father not tested

Feb 28, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_004992.4:c.568C>T (p.Arg190Cys) variant in MECP2 is observed in at least 2 unaffected individuals (GeneDx internal database, LabCorp Genetics Inc. internal database) (BS2). Quantitative immunofluorescence localization assays have shown that this variant impacts protein function (PMID: 29431277) (PS3_Supporting). The highest population frequency in gnomAD v4.1 is 0.00002 in the European (Finnish) population (BS1_Not Met). The p.Arg190Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID: 24776741) (PS2 - not met as patient was not described to have features of Rett syndrome). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.626). A missense variant (p.Arg190His) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5- not met). In summary, the p.Arg190Cys variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS3_Supporting) (MECP2 Specifications v3.0; curation approved on 02/28/2025).

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with cysteine at codon 190 of the MECP2 protein (p.Arg190Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587783137, ExAC 0.002%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with schizophrenia (PMID: 24776741). ClinVar contains an entry for this variant (Variation ID: 156667). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Apr 30, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage in a patient with schizophrenia in published literature, using alternate nomenclature R202C (McCarthy et al., 2014); Published functional studies suggest that R190C is damaging to MECP2 function in vitro and in cell lines (Sheikh et al., 2018); This variant is associated with the following publications: (PMID: 24776741, 29431277, 29655203)

MECP2-related disorder Uncertain:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MECP2 c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Cys. This variant was reported as a de novo finding in an individual with schizophrenia (reported as R202C in Table 1, McCarthy et al. 2014. PubMed ID: 24776741). An in vitro experimental study shoes that this variant impacts protein function (Sheikh et al. 2018. PubMed ID: 29431277). A different missense variant at this locus, p.Arg190His, has been seen in an individual with schizophrenia and has also been shown to impact protein function (Sheikh et al. 2018. PubMed ID: 29431277). This variant is reported in 0.0049% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.32		Loss of methylation at R190 (P = 0.0038)
MVP		0.98
ClinPred		0.82	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.83
Mutation Taster		=77/23	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: rs587783137; hg19: chrX-153296711;