rs61748404

Positions:

• chrX-154031373-G-C
• chrX-154031373-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2_Supporting PP4 PP3 PS4 PM1 PM5 PM6 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270424/MONDO:0010726/036

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 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 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.491C>G	p.Pro164Arg	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.455C>G	p.Pro152Arg	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.491C>G	p.Pro164Arg	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.455C>G	p.Pro152Arg	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:9

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Oct 05, 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 pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in ≥4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1).At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).This variant is absent from gnomAD (PM2_Supporting).Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PMID 21831886, PMID22923521) (PS3). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Pathogenic, criteria provided, single submitter	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 17, 2021	A heterozygous de novo missense variation in exon 3 of the MECP2 gene that results in the amino acid substitution of Arginine for Proline at codon 164 was detected. The observed variant c.491C>G (p.Pro164Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 29, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2018	Variant summary: MECP2 c.455C>G (p.Pro152Arg) results in a non-conservative amino acid change located in the methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 177980 control chromosomes (gnomAD). The variant, c.455C>G, has been reported in the literature in multiple individuals affected with Rett Syndrome, Classic (e.g. Cheadle 2000, Obata 2000, Huppke 2000, Philippe 2006, Buoni 2008). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a disrupted heterochromatin binding for the variant protein (e.g. Adegbola 2009, Sheikh 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as pathogenic, the other VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2023	Several functional studies have shown that P152R has a damaging effect by severely affecting heterochromatin clustering and repressing transcription (PMID: 12843318, 21831886, 22923521); Published functional study using in silico and in vitro approaches demonstrated that P152R had a significant destabilizing effect on the protein (PMID: 26418480); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21831886, 23859859, 22923521, 10767337, 27379843, 31785789, 32472557, 12030010, 31847883, 31440721, 31069529, 12843318, 32477112, 27929079, 26418480) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2020	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Rett Syndrome (PMID: 30573328 (2019), 29482495 (2018), 24508304 (2014), 24453408 (2013), 23859859 (2013), 23488948 (2013)). This variant has been reported to have a deleterious effect on MECP2 protein function (PMID: 21831886 (2011), 22923521 (2012), 27929079 (2016)). In addition, this variant has been detected in the de novo state in an individual with Rett Syndrome (PMID: 10767337 (2000)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2022	- -

not specified Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2018	The MECP2 c.455C>G; p.Pro152Arg variant (rs61748404) is reported in the literature in numerous individuals affected with Rett syndrome (Cheadle 2000, Maortua 2013, Sheen 2013, Rettbase) and has been reported to occur de novo (Cheadle 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 143579), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant at this codon (p.Arg152His) has been reported in an individual with Rett syndrome and is considered pathogenic (Sheikh 2016). The proline at codon 152 is highly conserved, and structural modeling suggests that the p.Pro152Arg variant disrupts local hydrogen bonding patterns (Kucukkal 2015). Further, biochemical analyses demonstrate that this variant destabilizes MECP2 protein (Kucukkal 2015), while expression of the p.Pro152Arg variant in cultured cells alters nuclear heterochromatin organization (Agarwal 2011, Casas-Delucchi 2012, Sheikh 2016). Based on available information, this variant is considered to be pathogenic. References: Link to Rettbase: https://www.rettsyndrome.org/ Agarwal N et al. MeCP2 Rett mutations affect large scale chromatin organization. Hum Mol Genet. 2011 Nov 1;20(21):4187-95. Casas-Delucchi CS et al. Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization. Nucleic Acids Res. 2012 Dec;40(22):e176. Cheadle JP et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Kucukkal TG et al. Impact of Rett Syndrome Mutations on MeCP2 MBD Stability. Biochemistry. 2015 Oct 20;54(41):6357-68. Maortua H et al. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). J Mol Diagn. 2013 Sep;15(5):723-9. Sheen V et al. Atypical features in MECP2 P152R-associated Rett syndrome. Pediatr Neurol. 2013 Aug;49(2):124-6. Sheikh TI et al. From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2. Sci Rep. 2016 Dec 8;6:38590. -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the MECP2 protein (p.Pro152Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 10814718, 11055898, 11241840, 15173251, 23859859). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143579). 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: 21831886, 22923521, 26418480, 27929079). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2018

The p.P152R pathogenic mutation (also known as c.455C>G), located in coding exon 3 of the MECP2 gene, results from a C to G substitution at nucleotide position 455. The proline at codon 152 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with Rett syndrome (Cheadle JP et al. Hum. Mol. Genet., 2000 Apr;9:1119-29; Buyse IM et al. Am. J. Hum. Genet., 2000 Dec;67:1428-36; Erlandson A et al. Eur Child Adolesc Psychiatry, 2001 Jun;10:117-21; Chae JH et al. J. Child Neurol., 2004 Jul;19:503-8; Fukuda T et al. Brain Dev., 2005 Apr;27:211-7; Lima FT et al. Arq Neuropsiquiatr, 2009 Sep;67:577-84; Das DK et al. Gene, 2013 Feb;515:78-83; Sheen V et al. Pediatr. Neurol., 2013 Aug;49:124-6). Expression of this mutation in Pmi28 mouse myoblasts demonstrated an increase in protein accumulation at chromocenters (Agarwal N et al. Hum. Mol. Genet., 2011 Nov;20:4187-95). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MECP2 NM_004992.3 exon 4 p.Pro152Arg (c.455C>G): This variant has been reported in the literature in at least 2 individuals with Rett syndrome, one of whom was reported as de novo (Cheadle 2000 PMID:10767337, Sheen 2013 PMID:23859859). In addition, this variant has been reported in several individuals with Rett syndrome or features of Rett syndrome by the RettBASE database (Christodoulou 2003 PMID:12673788). Furthermore, one publication suggests that this variant is one of the most common variants in reported cases (est. 1.41%) (Sheikh 2016 PMID:27929079). This variant is not present in large control databases and is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:143579). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. Other variants at this same codon (p.Arg152Leu, p.Arg152Ala, p.Arg152His) have been reported in the literature, supporting that this region has significance. Furthermore, this variant occurs in exon 4 of this gene. The vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. Loss of function has been established for this gene, but missense variants have been described as pathogenic as well (Philippe 2006 16473305). Functional studies also predict that this variant will impact the protein (Kudo 2003 PMID:12843318, Agarwal 2011 PMID:21831886, Casas-Delucchi 2012 PMID:22923521, Sheikh 2016 PMID:27929079). In summary, this variant is classified as pathogenic. -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D;D;.;.;.
Sift4G	Benign	0.073	T;D;.;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.92
MutPred		0.85		Gain of phosphorylation at S149 (P = 0.1297);.;Gain of phosphorylation at S149 (P = 0.1297);.;.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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: rs61748404; hg19: chrX-153296824;