rs61751449

Variant names:

• chrX-154030864-G-A
• rs61751449
• NM_001110792.2:c.1000C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030864-G-A
• chrX-154030864-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001110792.2(MECP2):​c.1000C>T​(p.Pro334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P334L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.86
• Publications: 18 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154030863-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 143754.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant X-154030864-G-A is Pathogenic according to our data. Variant chrX-154030864-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11843.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1000C>T	p.Pro334Ser	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.964C>T	p.Pro322Ser	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.1000C>T	p.Pro334Ser	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.964C>T	p.Pro322Ser	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rett syndrome Pathogenic:3

Apr 26, 2016

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: Likely 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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). It has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, PMID: 16966553, PMID: 30573328, PMID: 32370253, PMID: 30536762). Another missense variant in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5, CA270591). -

Oct 06, 2020

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 12, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 322 of the MECP2 protein (p.Pro322Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MECP2-related conditions (PMID: 16966553, 30536762). ClinVar contains an entry for this variant (Variation ID: 11843). 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 not expected to disrupt MECP2 protein function with a negative predictive value of 95%. This variant disrupts the p.Pro322 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10814718, 15526954, 17089071, 29718204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.55	D
PhyloP100		1.9
Sift4G	Benign	0.17	T
Vest4		0.43
MVP		0.98
ClinPred		0.78	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
Mutation Taster		=16/84	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: rs61751449; hg19: chrX-153296315;