rs267608455

Positions:

• chrX-154032220-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PP4 PM2_Supporting PS4_Supporting PS2 PM1

This summary comes from the ClinGen Evidence Repository: The p.Val122Met variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID:17089071) (PP4). The p.Val122Met variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in this individual. It is also reported in the mosaic state in a male patient with clinical features of Rett syndrome (PMID 28837158, internal database - GeneDx) and therefore confirmed to be de novo (PS2, PS4_supporting). The p.Val122Met variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val122Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Val122Met variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PM1, PS4_supporting, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270366/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: 7.50

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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• 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.400G>A	p.Val134Met	missense_variant	2/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.364G>A	p.Val122Met	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.400G>A	p.Val134Met	missense_variant	2/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.364G>A	p.Val122Met	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: 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, PMID 28837158 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate).ClinVar Variation ID: 143546 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 17089071 -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 18, 2008	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Val122Met variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 17089071) (PP4). The p.Val122Met variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in this individual. It is also reported in the mosaic state in a male patient with clinical features of Rett syndrome (PMID 28837158, internal database - GeneDx) and therefore confirmed to be de novo (PS2, PS4_supporting). The p.Val122Met variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val122Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Val122Met variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PM1, PS4_supporting, PM2_supporting, PP3, PP4). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2016

The V122M missense variant in the MECP2 gene has been reported previously as a de novo variant in a female patient with Rett syndrome (Li et al., 2007). The V122M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V122M variant is a conservative amino acid substitution. This substitution alters a conserved position predicted to be part of the hydrophobic core within the mCpG-binding domain (MBD) of the MECP2 protein (Wakefield et al., 1999). A different missense variant in the same codon (V122A) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with MECP2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Uncertain	0.012	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.92		Gain of disorder (P = 0.0761);.;Gain of disorder (P = 0.0761);.;Gain of disorder (P = 0.0761);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.96

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: rs267608455; hg19: chrX-153297671;