rs61748421

chrX-154031326-G-AchrX-154031326-G-T

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:37 O:1
• Conservation: PhyloP100: 2.57

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 195 pathogenic variants in the truncated region.
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 23.
• PP5: Variant X:154031326-G>A is Pathogenic according to our data. Variant chrX-154031326-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11828. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031326-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031326-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.538C>T	p.Arg180Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.502C>T	p.Arg168Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.538C>T	p.Arg180Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.502C>T	p.Arg168Ter	stop_gained	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

Rett syndrome Pathogenic:22Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	Variant summary: The MECP2 c.502C>T (p.Arg168X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate the transcriptional repression domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.710delG/p.Gly237fsX11). This variant is reported as one of the most common pathogenic variants in literature and clinical databases. The available clinical data and functional studies are consistent with pathogenic outcome for the variant. This variant is absent in 87628 control chromosomes. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jan 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Jun 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Feb 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 17, 2019	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PVS1, PS3, PM1, PM2, PP3 -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 02, 2023	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_VSTR, PS3, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Klinikum rechts der Isar	Jul 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Feb 02, 2022	- -
not provided, no assertion provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Jun 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011828.27). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 25, 2007	- -
Pathogenic, criteria provided, single submitter	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 17, 2021	A mosaic hemizygous (somatic mosaicism) nonsense variation in exon 3 of the MECP2 gene that results in premature truncation of the Arginine at codon 180. The observed variant c.538C>T(p.Arg180Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2(HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo (post-zygotic, somatic). In summary, the variant meets our criteria to be classified as a pathogenic variant. -

not provided Pathogenic:11

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2020	The MECP2 c.502C>T; p.Arg168Ter variant (rs61748421) is one of the most common variants identified in individuals with Rett syndrome (see link, Pidcock 2016, Wan 1999), and is shown to have impaired functional capabilities (Bissonnette 2014, Delepine 2013, Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11828). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to RettBASE database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Bissonnette JM et al. Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. Neuroscience. 2014 May 16;267:166-76. Delepine C et al. MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett. 2013 Jan 16;587(2):245-53. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wan M et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec;65(6):1520-9. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Karolinska University Hospital, Karolinska University Hospital	Dec 08, 2016	- -
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	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2018	- -
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	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	PerkinElmer Genomics	Sep 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	Recurrent pathogenic variant that accounts for 8-9% of MECP2 pathogenic variants (Percy et al., 2007); Typically associated with classic Rett syndrome but also identified in females with atypical Rett syndrome (Halbach et al., 2012; Neul et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 319 amino acids are lost, and other loss-of-function variants have been reported downstream (Stenson et al., 2014; RettBASE); Published functional studies indicate this variant truncates all of the transcriptional repression domain (TRD) and impairs normal protein function (Yusufzai et al., 2000; Bissonnette et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26175308, 24626160, 10577905, 24283265, 23270700, 24511209, 23238081, 25541993, 18337588, 22190343, 15228575, 28394409, 16077729, 28333917, 18174548, 30564305, 29655203, 31164858, 31209962, 31144778, 31535341, 32393352, 32631363, 11058114, 33144682, 12030010, 31130284, 33258288) -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2022

This sequence change creates a premature translational stop signal (p.Arg168*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 10577905, 23270700, 24511209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11828). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 24283265, 24626160, 25541993). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

The p.R168* pathogenic mutation (also known as c.502C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 502. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation is one of eight common Rett syndrome mutations and has been associated with earlier onset and more severe symptoms than other mutations; however, it has also been detected in unaffected females (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Cuddapah VA et al. J. Med. Genet., 2014 Mar;51:152-8; Knight O et al. Brain Dev., 2013 Nov;35:912-20). In one study, in vitro and in vivo studies showed that this mutation alters expression of downstream genes, induces expansion of lateral neurons, and its mutant protein is able to bind to methylated DNA, suggesting that this mutation may function in a dominant negative manner (Neul JL et al. Neuroscientist, 2004 Apr;10:118-28). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Global developmental delay;C1836830:Developmental regression Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.73

D

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

38

Dann

Uncertain

1.0

DEOGEN2

Benign

0.11

T

FATHMM_MKL

Uncertain

0.93

D

LIST_S2

Benign

0.49

T

MetaRNN

Uncertain

0.50

D

MutationTaster

Benign

1.0

A;A;A

Sift4G

Uncertain

0.0080

D

Vest4

0.47

MVP

0.94

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61748421; hg19: chrX-153296777; COSMIC: COSV100318642; COSMIC: COSV100318642;