rs61748390

chrX-154031427-G-AchrX-154031427-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):c.437C>T(p.Ser146Phe) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S146C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031427-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-154031427-G-A is Pathogenic according to our data. Variant chrX-154031427-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143563.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031427-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.437C>T	p.Ser146Phe	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.401C>T	p.Ser134Phe	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.437C>T	p.Ser146Phe	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.401C>T	p.Ser134Phe	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Ser134Phe variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 2 individuals with Rett syndrome (PMID 15737703, internal database - GeneDx) (PS2, PP4). The p.Ser134Phe variant has been observed in at least 1 other individual with Rett syndrome (PMID 21160487) (PS4_moderate). A pathogenic missense variant (p.Ser134Cys) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588, 10767337, 23696494, 22182064) (PM5). The p.Ser134Phe variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Ser134Phe 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.Ser134Phe variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PS4_moderate, PM1, PM5, PM2_supporting, PP3, PP4). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Nov 01, 2011	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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: 15737703, ClinVar Variation ID: 143563) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Another missense variant in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PMID: 15737703, 15526954, 21160487, ClinVar Variation ID: 143563) 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 15737703 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2016

The de novo S134F pathogenic variant in the MECP2 gene has been reported previously in two unrelated individuals with Rett syndrome (Fukuda et al., 2005; Hadzsiev et al., 2011). In addition, pathogenic missense variants at this same position (S134P and S134C) have been reported in the Human Gene Mutation Database in association with Rett syndrome (Stenson et al., 2014; RettBASE), supporting the functional importance of this region of the protein. The S134F 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 S134F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the methyl CpG-binding domain (MBD) and is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret S134F as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D;D;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.95		Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.99

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: rs61748390; hg19: chrX-153296878;