chrX-154030924-G-A

Position:

• chrX-154030924-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.940C>T​(p.Pro314Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P314L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 8.99

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 14 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000453960.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154030923-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143738.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant X-154030924-G-A is Pathogenic according to our data. Variant chrX-154030924-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.940C>T	p.Pro314Ser	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.904C>T	p.Pro302Ser	missense_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.940C>T	p.Pro314Ser	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.904C>T	p.Pro302Ser	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 25, 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 likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Another missense variant in the same codon has been classified as pathogenic (PM5) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). (PMID 17387578 ClinVar Variation ID: 143735) . -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Nov 01, 2007	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro302 amino acid residue in MECP2. Other variants that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 10767337, 10814718, 10814719, 15737703), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with Rett syndrome (PMID: 17387578), and has also been observed to be de novo in an individual affected with clinical features of MECP2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 143735). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 302 of the MECP2 protein (p.Pro302Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 30, 2020

The MECP2 c.904C>T; p.Pro302Ser variant (rs61751373) is reported in the literature an individual with classical Rett syndrome (Zahorakova 2007). Additionally, other amino acid substitutions at this codon (p.Pro302Leu, p.Pro302Ala, p.Pro302Arg, p.Pro302His, p.Pro302Thr) have been reported in individuals with Rett syndrome (see link to RettBASE and references therein). The c.904C>T; p.Pro302Ser is reported in the ClinVar database (Variation ID: 143735) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 302 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this amino acid has been implicated in binding a co-repressor complex and one variant at this position, p.Pro302Arg, abolishes this interaction (Lyst 2013). Considering available information, this variant is classified as likely pathogenic. References: RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52(4):342-8. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.66	D
MutationTaster	Benign	1.0	D;D
Sift4G	Benign	0.17	T
Vest4		0.48
MVP		0.96
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61751373; hg19: chrX-153296375;