X-154031154-G-C

Position:

• chrX-154031154-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):​c.710C>G​(p.Pro237Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.89

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-154031154-G-C is Pathogenic according to our data. Variant chrX-154031154-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 143653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031154-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.710C>G	p.Pro237Arg	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.674C>G	p.Pro225Arg	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.710C>G	p.Pro237Arg	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.674C>G	p.Pro225Arg	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 14, 2023	PS2, PS3, PS4, PM2, PP3 -
Pathogenic, no assertion criteria provided	curation	RettBASE	May 18, 2012	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 22, 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: 17089071, 10767337). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 31427717, 17407838, 17387578, 17089071, 16473305, 19133691, 18842453, 10767337, 11245712). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	Published functional studies demonstrate a damaging effect (Guy et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33084218, 10854091, 17089071, 10805343, 17387578, 21160487, 26984561, 11245712, 22190343, 26469135, 22139899, 15880509, 18056689, 19133691, 11524741, 29782864, 12180070, 18842453, 21954873, 12655490, 11214906, 12746405, 15675358, 29718204, 17142618, 16690727, 16473305, 12111643, 12075485, 10767337) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 14, 2016	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the MECP2 protein (p.Pro225Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with either classic or atypical Rett syndrome (PMID: 10767337, 10854091, 11524741, 12075485, 12111643, 16473305, 16690727, 17142618). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. This variant disrupts the p.Pro225 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12615169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Seizure;C0425492:Irregular respiration;C1836830:Developmental regression;C1837397:Severe global developmental delay;C1854882:Absent speech Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

MECP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The MECP2 c.674C>G variant is predicted to result in the amino acid substitution p.Pro225Arg. This variant was reported in multiple individuals with Rett syndrome, epilepsy or intellectual disability and has been described as a recurrent causative variant documented as de novo in at least one patient (Cheadle et al. 2000. PubMed ID: 10767337; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S2, Dong et al. 2020. PubMed ID: 32005694; Table S1, Wen et al. 2020. PubMed ID: 32472557). In vitro functional studies found this variant interferes with protein function through decreased stability or conformational changes (Guy et al. 2018. PubMed ID: 29718204). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D;D;.;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Benign	0.12	T;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.89
MutPred		0.84		Gain of MoRF binding (P = 0.0042);.;Gain of MoRF binding (P = 0.0042);.;
MVP		1.0
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
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: rs61749715; hg19: chrX-153296605;