X-154032212-C-A

Position:

• chrX-154032212-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PS2 PS1 PM1

This summary comes from the ClinGen Evidence Repository: The c.372G>T (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the mosaic state in a male patient with a neurodevelopmental phenotype consistent with the MECP2 gene (internal database - Invitae) and therefore confirmed to be de novo (PS2). The c.372G>T (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>T (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). The c.372G>C variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (PMID 10991688, 12843318) (PS1). In summary, the c.372G>T (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PS2, PM1, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270371/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 0.677

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 11 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.408G>T	p.Leu136Phe	missense_variant	2/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.372G>T	p.Leu124Phe	missense_variant	3/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.408G>T	p.Leu136Phe	missense_variant	2/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.372G>T	p.Leu124Phe	missense_variant	3/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 15, 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: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (PS1).(PMID 10991688, 12843318) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 17089071 At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). 17089071 This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The c.372G>T (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the mosaic state in a male patient with a neurodevelopmental phenotype consistent with the MECP2 gene (internal database - Invitae) and therefore confirmed to be de novo (PS2). The c.372G>T (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>T (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). The c.372G>C variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (PMID 10991688, 12843318) (PS1). In summary, the c.372G>T (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PS2, PM1, PM2_supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 18, 2008	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318). 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 expected to disrupt MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143550). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10991688). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 124 of the MECP2 protein (p.Leu124Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;T;T;T;T;T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.045	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.93	N;N;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.089	T;T;.;.;.;.;.
Sift4G	Uncertain	0.038	D;D;D;D;.;T;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.91
MutPred		0.89		Loss of MoRF binding (P = 0.117);.;Loss of MoRF binding (P = 0.117);.;Loss of MoRF binding (P = 0.117);.;.;
MVP		0.99
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61755763; hg19: chrX-153297663; COSMIC: COSV105884113; COSMIC: COSV105884113;