rs179363900

chrX-154031374-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_001110792.2(MECP2):c.490C>G(p.Pro164Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,035 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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. P164R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:2
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001110792.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031373-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 143579.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-154031374-G-C is Pathogenic according to our data. Variant chrX-154031374-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11844.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031374-G-C is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.490C>G	p.Pro164Ala	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.454C>G	p.Pro152Ala	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.490C>G	p.Pro164Ala	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.454C>G	p.Pro152Ala	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111947 Hom.: 0 Cov.: 23 AF XY: 0.0000586 AC XY: 2 AN XY: 34119

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098088 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 3 AN XY: 363442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111947 Hom.: 0 Cov.: 23 AF XY: 0.0000586 AC XY: 2 AN XY: 34119

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database) (PP1_Moderate). The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro152Ala variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS3_supporting, PP1_moderate, PM1, PM5, PP3). -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3, PMID: 18989701). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Another missense variant (c.491C>G, p.Pro164Arg, ClinVar Variation ID: 143579) in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Dec 21, 2023	Other patients with the same variant not presenting phenotype. -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 04, 2009	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 14, 2020	ACMG codes:PS3; PS4M; PM1; PM2; PM5; PP4 -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 31, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 152 of the MECP2 protein (p.Pro152Ala). This variant is present in population databases (rs179363900, gnomAD no frequency). This missense change has been observed in individual(s) with mild forms of Rett syndrome (PMID: 18989701, 27929079, 29655203). ClinVar contains an entry for this variant (Variation ID: 11844). 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) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 18989701, 26842955, 27929079). This variant disrupts the p.Pro152 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 11241840, 27929079). 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. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	Reported in a female with pervasive developmental disorder, obesity, abnormal EEG, and inherited from her father with learning disabilities and obesity (Adegbola et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27929079, 29655203, 26842955, 18989701, 33258288) -

Rett syndrome, zappella variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2009

- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.0	L;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	D;D;.;.;.
REVEL	Pathogenic	0.87
Sift	Benign	0.046	D;D;.;.;.
Sift4G	Benign	0.50	T;T;.;T;T
Polyphen		0.90	P;P;.;.;.
Vest4		0.76
MutPred		0.85		Loss of disorder (P = 0.0974);.;Loss of disorder (P = 0.0974);.;.;
MVP		1.0
ClinPred		0.77	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.94

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: rs179363900; hg19: chrX-153296825;