X-154030992-G-A

Position:

• chrX-154030992-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Ala279Val variant in MECP2 (NM_004992.4) has been observed in at least 5 individuals with a clinical phenotype consistent with Rett syndrome (PMID:15526954, ClinVar, internal database - Invitae) (PS4, PP4). The p.Ala279Val variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala279Val variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270535/MONDO:0010726/036

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 3.21

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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.872C>T	p.Ala291Val	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.836C>T	p.Ala279Val	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.872C>T	p.Ala291Val	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.836C>T	p.Ala279Val	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	curation	RettBASE	Dec 03, 2007	- -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 25, 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 a variant of uncertain significance. At least the following criteria are met: Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID 15526954 This variant is absent from gnomAD (PM2_Supporting). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 30, 2024	The p.Ala279Val variant in MECP2 (NM_004992.4) has been observed in at least 5 individuals with a clinical phenotype consistent with Rett syndrome (PMID: 15526954, ClinVar, internal database - Invitae) (PS4, PP4). The p.Ala279Val variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala279Val variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM2_supporting, PP4). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the MECP2 protein (p.Ala279Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 15526954). ClinVar contains an entry for this variant (Variation ID: 143710). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 08, 2021

The hemizygous c.872C>T (p.Ala291Val) variant identified in the MECP2 gene is the substitution of a moderately conserved Alanine for Valine at amino acid 291/499 (exon 3/3) in transcript NM_001110792.2. MECP2 is alternatively spliced, and this variant is also called c.836C>T (p.Ala279Val) when annotated from transcript NM_004992.3 (NP_004983.1). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.127) and Benign (REVEL; score:0.492) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:143710) and has been identified in three affected individuals in a single publication in the literature [PMID:15526954]. The p.Ala291 residue is within the second Transcription Repression Domain (TRD) of MECP2 (UniProtKB:P51608; PMID:28544139), where other pathogenic missense variants have been identified [PMID:28544139]. The hemizygous c.872C>T (p.Ala291Val) variant identified in the MECP2 gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.92	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.13	N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.053	B;B;.
Vest4		0.41
MutPred		0.70		Gain of methylation at K284 (P = 0.1564);.;.;
MVP		1.0
ClinPred		0.34	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.070
gMVP		0.87

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: rs61750249; hg19: chrX-153296443;