rs267608387

Positions:

• chrX-154031448-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4 PM2_Supporting PM6_Strong PM1 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The p.Pro127Leu variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID:16225173, 22182064) (PM6_strong, PP4). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID:11245712, 16473305, 11960578, internal database - Invitae) (PS4). The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2 (PMID:21326358, 23770565) (PM1). The p.Pro127Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro127Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4, PM1, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270373/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 9.46

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 13 ACMG points.

• PS4: 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.
• PP3: 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.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.380C>T	p.Pro127Leu	missense_variant, splice_region_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.416C>T	p.Pro139Leu	missense_variant, splice_region_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.380C>T	p.Pro127Leu	missense_variant, splice_region_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 09, 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: 16225173, 17089071, 22182064 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 16473305, 16225173, 11245712, 20207612, 11960578, 17089071). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jul 13, 2010	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Pro127Leu variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, 22182064) (PM6_strong, PP4). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID: 11245712, 16473305, 11960578, internal database - Invitae) (PS4). The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2 (PMID: 21326358, 23770565) (PM1). The p.Pro127Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro127Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4, PM1, PM2_supporting, PP3, PP4). -
Pathogenic, no assertion criteria provided	clinical testing	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this this missense change did not affect MECP2 accumulation at chromocenters or MECP2 transcriptional repressive activity in cultured cells (PMID: 21831886, 12843318). This variant has been reported in two individuals affected with classical Rett syndrome (PMID: 16225173, 11960578) and an individual affected with the rare preserved speech variant of Rett syndrome (PMID: 11245712). This variant has also been shown to arise de novo in an individual affected with Rett syndrome (PMID: 20376788, 22182064). ClinVar contains an entry for this variant (Variation ID: 143552). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 127 of the MECP2 protein (p.Pro127Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.8	D;D;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.69
MutPred		0.91		Loss of catalytic residue at P127 (P = 0.0091);.;Loss of catalytic residue at P127 (P = 0.0091);.;Loss of catalytic residue at P127 (P = 0.0091);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.95

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: rs267608387; hg19: chrX-153296899;