X-154032212-C-G

Variant names:

• chrX-154032212-C-G
• rs61755763
• NM_001110792.2:c.408G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PM6 PM2_Supporting PM1 PS1

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
• Publications: 5 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: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.408G>C	p.Leu136Phe	missense_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.372G>C	p.Leu124Phe	missense_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.408G>C	p.Leu136Phe	missense_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.372G>C	p.Leu124Phe	missense_variant	Exon 3 of 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

Mar 14, 2024

Centre for Population Genomics, CPG

Significance: 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 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) -

Jan 21, 2008

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Oct 11, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

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;.;.;.;.;.;.
PhyloP100		0.68
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
PromoterAI		0.053	Neutral
Varity_R		0.58
gMVP		0.92
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs61755763; hg19: chrX-153297663;