X-154032212-C-G

Position:

• chrX-154032212-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM6 PS1 PM2_Supporting PM1 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.372G>C (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 10991688) (PM6). The c.372G>C (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>C (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 heterochromatin binding assay and in vitro transcriptional repression assay have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). The c.372G>T variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (internal database - Invitae) (PS1). In summary, the c.372G>C (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PM1, PM6, PM2_supporting, PS3_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270369/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 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]

MECP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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.
• PM6: 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>C	p.Leu136Phe	missense_variant	2/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.372G>C	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>C	p.Leu136Phe	missense_variant	2/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.372G>C	p.Leu124Phe	missense_variant	3/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The c.372G>C (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 10991688) (PM6). The c.372G>C (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>C (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 heterochromatin binding assay and in vitro transcriptional repression assay have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). The c.372G>T variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (internal database - Invitae) (PS1). In summary, the c.372G>C (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PM1, PM6, PM2_supporting, PS3_supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jan 21, 2008	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 14, 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 at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 15737703, 10991688) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID: 15737703, 11738864, 10991688, 20728410) This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). (PMID: 36253345, 12843318) -

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	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;T;T;T;T;T
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.045	N;.;.;.;.;.;.
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		0.60	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;