X-154030911-C-T

Position:

• chrX-154030911-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.953G>A​(p.Arg318His) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318C) 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:9
• Conservation: PhyloP100: 5.36

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 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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-154030912-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11824.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant X-154030911-C-T is Pathogenic according to our data. Variant chrX-154030911-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030911-C-T is described in Lovd as [Pathogenic]. Variant chrX-154030911-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.953G>A	p.Arg318His	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.917G>A	p.Arg306His	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.953G>A	p.Arg318His	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.917G>A	p.Arg306His	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 30, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Feb 15, 2011	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Dec 06, 2023	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 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).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).(PubMed: 11055898‚ 15057977‚ 16473305, 10767337, 23921973 ClinVar database Variation ID: 143746) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Medical Genetics, University of Torino	Oct 09, 2022	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10991688, 14649554, 16473305, 23770565, 24511209, 24970834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 143746). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 23921973). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MECP2 protein (p.Arg306His). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate that the p.R306H variant abolishes binding of MECP2 to DNA (Heckman et al., 2014); This variant is associated with the following publications: (PMID: 31780880, 11055898, 12655490, 11214906, 15057977, 16473305, 24970834, 10767337, 23921973) -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.79		Loss of MoRF binding (P = 0.0304);.;
MVP		1.0
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
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: rs61751443; hg19: chrX-153296362;