VCV000011819.58 - ClinVar

NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

43 submissions

41 submitters

9 conditions

Reviewed by expert panel

Pathogenic

Mar 2021 by ClinGen Rett a… FDA Recognized Database

for Rett syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter)

Variation ID: 11819 Accession: VCV000011819.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154030948 (GRCh38) [ NCBI UCSC ] X: 153296399 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 22, 2015	Nov 24, 2024	Mar 26, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110792.2:c.916C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001104262.1:p.Arg306Ter	nonsense
NM_004992.4:c.880C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004983.1:p.Arg294Ter	nonsense
NM_001316337.2:c.601C>T	NP_001303266.1:p.Arg201Ter	nonsense
NM_001369391.2:c.601C>T	NP_001356320.1:p.Arg201Ter	nonsense
NM_001369392.2:c.601C>T	NP_001356321.1:p.Arg201Ter	nonsense
NM_001369393.2:c.601C>T	NP_001356322.1:p.Arg201Ter	nonsense
NM_001369394.2:c.601C>T	NP_001356323.1:p.Arg201Ter	nonsense
NM_001386137.1:c.211C>T	NP_001373066.1:p.Arg71Ter	nonsense
NM_001386138.1:c.211C>T	NP_001373067.1:p.Arg71Ter	nonsense
NM_001386139.1:c.211C>T	NP_001373068.1:p.Arg71Ter	nonsense
NM_004992.3:c.[880C>T]
NC_000023.11:g.154030948G>A
NC_000023.10:g.153296399G>A
NG_007107.3:g.111156C>T
LRG_764:g.111156C>T
LRG_764t1:c.916C>T	LRG_764p1:p.Arg306Ter
LRG_764t2:c.880C>T	LRG_764p2:p.Arg294Ter
AJ132917.1:c.880C>T

... more HGVS ... less HGVS

Protein change

R294*, R306*, R201*, R71*

Other names

NP_004983.1:p.Arg294*
p.R294X:CGA>TGA
NM_001110792.2(MECP2):c.916C>T

Canonical SPDI

NC_000023.11:154030947:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA121700 OMIM: 300005.0011 dbSNP: rs61751362 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MECP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1904	2232

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Rett syndrome	Pathogenic (21)	reviewed by expert panel	Mar 26, 2021	RCV000012590.53
Autism, susceptibility to, X-linked 3	Pathogenic; risk factor (2)	no assertion criteria provided	Dec 5, 2013	RCV000012591.7
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Sep 22, 2023	RCV000081215.36
Severe neonatal-onset encephalopathy with microcephaly	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000474366.9
Autism, susceptibility to, X-linked 3 Rett syndrome Severe neonatal-onset encephalopathy with microcephaly Syndromic X-linked intellectual disability Lubs type X-linked intellectual disability-psychosis-macroorchidism syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 21, 2022	RCV000515413.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 5, 2021	RCV000624805.5
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420261.3
Syndromic X-linked intellectual disability Lubs type	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV003984806.3
MECP2-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV004545726.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 26, 2021)	reviewed by expert panel (ClinGen RettAS ACMG Specifications V1) Method: curation	Rett syndrome (X-linked inheritance) Affected status: unknown Allele origin: germline	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel FDA Recognized Database Accession: SCV001711975.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ede88874-946c-4213-9897-197e908f3c6d Comment: The p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where … (more) The p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting). (less)
Pathogenic (Mar 16, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885678.1 First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019	Comment: The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to … (more) The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to RettBASE below and references therein, Cheadle 2000, Pidcock 2016, Wen 2017, Wang 2016). Additionally, the variant protein is reported to have lowered expression, to have slightly reduced stability, and to be unable to repress transcription (Wen 2017, Yusufzai 2000). The variant is reported in the ClinVar database (Variation ID: 11819). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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. Considering available information, this variant is classified as pathogenic. References: Link to RettBase variants: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic 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. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wen Z et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017 Aug 3;8:43. Wang T et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. Yusufzai TM and Wolffe AP. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. (less)
Pathogenic (Feb 07, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449947.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 1
Pathogenic (Dec 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Rett syndrome Affected status: yes Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI WGS Accession: SCV001870338.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: ACMG codes:PVS1,PS3,PS4,PM2,PP5 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present)
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	DASA Accession: SCV002061284.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022	Publications: PubMed (13) PubMed: 31535341‚ 28465761‚ 26800272‚ 23270700‚ 16473305‚ 18332345‚ 11241840‚ 15737703‚ 19722030‚ 29046627‚ 23810759‚ 11058114‚ 26604147 Comment: The c.880C>T;p.(Arg294) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product … (more) The c.880C>T;p.(Arg294) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11819; PMID: 31535341; 28465761; 26800272; 23270700; 16473305; 18332345; 11241840; 15737703; 19722030; 29046627) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history(PMID: 23810759) - PS2. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11058114; 26604147) - PS3_moderate. This variant is not present in population databases (rs61751362, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073116.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: The stop gained p.R294* in MECP2 (NM_004992.3) has been reported multiple times in females affected with Rett syndrome and is also present in the Rett … (more) The stop gained p.R294* in MECP2 (NM_004992.3) has been reported multiple times in females affected with Rett syndrome and is also present in the Rett database (Boban et al; Wen Z et al). It has shown to promote apoptosis of identified neurons in vivo (Williams A et al). It has been submitted to the ClinVar database as Pathogenic. The p.R294* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Global developmental delay (present) , Attention deficit hyperactivity disorder (present)
Pathogenic (Jul 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579312.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1_STR, PS2, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome (X-linked inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807253.2 First in ClinVar: May 03, 2018 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 10767337 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with global delays and … (more) This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with global delays and hypotonia (less)
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability-psychosis-macroorchidism syndrome Syndromic X-linked intellectual disability Lubs type Autism, susceptibility to, X-linked 3 Severe neonatal-onset encephalopathy with microcephaly Rett syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611280.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Mar 28, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220019.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (10) PubMed: 10767337‚ 31535341‚ 11241840‚ 11058114‚ 23270700‚ 27159028‚ 27255190‚ 10854091‚ 12770674‚ 18332345 Comment: This variant causes the premature termination of MECP2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with Rett syndrome … (more) This variant causes the premature termination of MECP2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with Rett syndrome (PMID: 11241840 (2001), 23270700 (2013), 31535341 (2020)). In addition, a functional study reported this variant resulted in a damaging effect on protein function (PMID: 11058114 (2000)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 19, 2015)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: de novo	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236516.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000248001.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Jan 01, 2015)	criteria provided, single submitter (Fieremans et al. (Hum Mutat 2016)) Method: literature only	Rett syndrome (Sporadic) Affected status: yes Allele origin: unknown	Center for Human Genetics, University of Leuven Accession: SCV000268070.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015	Publications: PubMed (1) PubMed: 27159028 Number of individuals with the variant: 1 Clinical Features: Intellectual disability (present) , Microcephaly (present) , Spastic quadriplegia (present) Family history: no Sex: female Geographic origin: Europe
Pathogenic (Jul 12, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: de novo	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000537183.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 Comment: p.Arg294*	Publications: PubMed (8) PubMed: 23696494‚ 20031356‚ 10944854‚ 11245712‚ 12180070‚ 11214906‚ 1105898‚ 12770674 Number of individuals with the variant: 1 Age: 10-19 years Sex: female
Pathogenic (Jan 31, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Rett syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698546.1 First in ClinVar: Mar 03, 2018 Last updated: Mar 03, 2018	Publications: PubMed (10) PubMed: 11058114‚ 10991688‚ 15173251‚ 11462237‚ 10944854‚ 10767337‚ 11524741‚ 10814718‚ 10814719‚ 15526954 Comment: Variant summary: The MECP2 c.880C>T (p.Arg294X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense … (more) Variant summary: The MECP2 c.880C>T (p.Arg294X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1079C>A/p.Ser360X)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87847 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional study proved mutant protein R294X with loss of function (Yusufzai_ 2000). Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781713.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Pathogenic (Mar 28, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842739.1 First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018	Publications: PubMed (8) PubMed: 10767337‚ 11058114‚ 23270700‚ 27159028‚ 27255190‚ 10854091‚ 12770674‚ 18332345
Pathogenic (Nov 19, 2013)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230269.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 Number of individuals with the variant: 10 Sex: mixed
Pathogenic (Dec 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428755.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (X-linked inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446766.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Hypotonia (present) , Global developmental delay (present) , Motor delay (present) , Absent speech (present) Sex: female
Pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622681.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate Clinical Features: Global developmental delay (present) , Fetal growth restriction (present) , Motor delay (present) , Abnormal facial shape (present) , Plagiocephaly (present) , Cerebral arteriovenous malformation … (more) Global developmental delay (present) , Fetal growth restriction (present) , Motor delay (present) , Abnormal facial shape (present) , Plagiocephaly (present) , Cerebral arteriovenous malformation (present) , Periventricular leukomalacia (present) , Delayed speech and language development (present) , Short attention span (present) , Compulsive behaviors (present) (less) Sex: female
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome (X-linked inheritance) Affected status: yes Allele origin: de novo	Suma Genomics Accession: SCV001837641.1 First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002573202.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (6) PubMed: 15737703‚ 21982064‚ 19722030‚ 10767337‚ 11241840‚ 11960578 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal … (more) The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11960578, 15737703, 19722030, 21982064). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11241840). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011819/ PMID: 10767337/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Infantile muscular hypotonia (present) , Global developmental delay (present) , Delayed speech and language development (present) , Decreased body weight (present) , Failure to thrive … (more) Infantile muscular hypotonia (present) , Global developmental delay (present) , Delayed speech and language development (present) , Decreased body weight (present) , Failure to thrive (present) , Facial grimacing (present) , Congenital unilateral hypoplasia of depressor anguli oris (present) , Moon facies (present) , Triangular face (present) , Short neck (present) , Microcephaly (present) , Hyperpigmentation of eyelid (present) , Deeply set eye (present) , Short philtrum (present) , High forehead (present) , Low-set ears (present) , Pectus excavatum (present) , Clinodactyly of the 5th finger (present) , 2-3 toe syndactyly (present) , Pes planus (present) , Pes valgus (present) , Motor stereotypies (present) (less)
Pathogenic (Feb 26, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000191049.12 First in ClinVar: Nov 01, 2014 Last updated: Mar 04, 2023	Comment: Common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007); Observed in females with both classic and atypical Rett … (more) Common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007); Observed in females with both classic and atypical Rett syndrome, often associated with a milder clinical presentation, and has been identified in a male with progressive microcephaly, developmental regression, and a movement disorder (RettBASE; Neul et al., 2008; Lundvall et al., 2006); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 193 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it is defective in promoting nucleosome-nucleosome bridging (Yusufzai et al., 2000; Nikitina et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11058114, 26604147, 10991688, 17660293, 23270700, 27159028, 27824329, 10767337, 27255190, 29321033, 28785396, 29421650, 29595472, 29056246, 16077729, 26175308, 17420824, 11738864, 18337588, 17236109, 18174548, 30693677, 30564305, 30536762, 31209962, 31535341, 32105570, 32472557, 32005694, 33994118, 12030010, 31130284, 31031587) (less)
Pathogenic (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Severe neonatal-onset encephalopathy with microcephaly Syndromic X-linked intellectual disability Lubs type Autism, susceptibility to, X-linked 3 X-linked intellectual disability-psychosis-macroorchidism syndrome Rett syndrome Rett syndrome Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920186.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: This variant has been reported in the literature in numerous individuals with Rett syndrome, including males, and as de novo in at least 1 individual … (more) This variant has been reported in the literature in numerous individuals with Rett syndrome, including males, and as de novo in at least 1 individual with autism spectrum disorder (ASD) (Selected publications: Cheadler 2000 PMID:10767337, Yamashita 2001 PMID:11738864, Jian 2005 PMID:16077729, Lundvall 2006 PMID:17236109, Stachon 2007 PMID:17420824, Wen 2017 PMID:28785396). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11819). Functional studies support that this variant will impact the protein, suggesting repression of transcription and instability (Yusufzai 2000 PMID:11058114). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or abnormal protein. Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However, the vast majority of pathogenic variants in this gene (including this variant) 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 PMID:16473305). In summary, this variant is classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MECP2-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046412.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant is also known as c.880C>T (p.Arg294Ter) due to use of an alternate transcript. This nonsense variant found in exon 4 of 4 is … (more) This variant is also known as c.880C>T (p.Arg294Ter) due to use of an alternate transcript. This nonsense variant found in exon 4 of 4 is predicted to result in truncation of the MeCP2 protein. This variant has been previously reported in individuals with MECP2-related disorders (PMID:16473305, 11241840, 15737703, 19722030, 11960578, 21982064). Functional studies have shown that the c.916C>T (p.Arg306Ter) variant destabilizes the MeCP2 protein and expression of the truncated protein in-vitro results in increased apoptosis levels (PMID: 11058114, 27442528, 28785396). The c.916C>T (p.Arg306Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.916C>T (p.Arg306Ter) variant is classified as Pathogenic. (less)
Pathogenic (Aug 14, 2023)	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022)) Method: curation	Rett syndrome (X-linked inheritance) Affected status: unknown Allele origin: germline	Centre for Population Genomics, CPG Accession: SCV004098855.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4f9581c4-3218-4790-a62d-dae2c9df284f Comment: 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 … (more) 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 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 with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). 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 (PS3_supporting). (less)
Pathogenic (Aug 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823546.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Severe neonatal-onset encephalopathy with microcephaly Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544614.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (11) PubMed: 11241840‚ 15737703‚ 16473305‚ 17236109‚ 18332345‚ 19722030‚ 23270700‚ 11058114‚ 26604147‚ 27442528‚ 28785396 Comment: This sequence change creates a premature translational stop signal (p.Arg294) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg294) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 193 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 individuals with Rett syndrome (PMID: 11241840, 15737703, 16473305, 17236109, 18332345, 19722030, 23270700). ClinVar contains an entry for this variant (Variation ID: 11819). 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, 26604147, 27442528, 28785396). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Syndromic X-linked intellectual disability Lubs type Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801241.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Pathogenic (Oct 05, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000741622.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 10767337‚ 11058114‚ 14729826‚ 19234536‚ 20815036‚ 26175308‚ 28785396 Comment: The c.880C>T (p.R294) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position … (more) The c.880C>T (p.R294) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 880. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 294. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 38% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in many females with classic Rett syndrome. In addition, several studies show that this pathogenic variant is associated with a milder phenotype including, but not limited to: a later age at diagnosis (5-6 years of age), delayed onset of regression, later onset of stereotypical behaviors, more retention of words and hand function, and ambulatory ability (Cheadle, 2000; Fieremans, 2016; Pidcock, 2016; Wen, 2017; Colvin, 2004; Fehr, 2010). The p.R294* amino acid is located within the transcription repression domain, which normally binds methylated DNA in the context of chromatin, leading to long-term transcriptional repression (Hite, 2009). Functional analysis demonstrated that the p.R294* alteration retains DNA binding capabilities at levels comparable to those of the wild-type protein, but failed to repress DNA transcription (Yusufzai, 2000). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Oct 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399323.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 27442528 Comment: Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss and gain of function are … (more) Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene, where both protein instability and increased cell death have been demonstrated (OMIM, PMID: 27442528). (N) 0104 - Mechanism of disease for this gene is dominant negative. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 4 of 4). (P) 0301 - Variant is absent from gnomAD. (P) 0601 - Variant affects at the well established (essential) functional C-terminal region (PMID: 27442528). (P) 0701 - Comparable variants also predicted to result in a truncated protein, have very strong previous evidence for pathogenicity in patients with Rett syndrome (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in multiple de novo individuals with Rett syndrome (Decipher, ClinVar). (P) 0905 - No published segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where both animal models and transfected cell lines demonstrated increased cell death (PMID: 27442528). (P) 1204 - De Novo Variant (Parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (Sep 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413456.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: PM2, PS2_very_strong, PS4, PVS1 Number of individuals with the variant: 1
risk factor (Mar 11, 2008)	no assertion criteria provided Method: literature only	AUTISM, SUSCEPTIBILITY TO, X-LINKED 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032826.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 10854091‚ 18332345‚ 12770674 Comment on evidence: Rett Syndrome De Bona et al. (2000) identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated … (more) Rett Syndrome De Bona et al. (2000) identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated patients with Rett syndrome (RTT; 312750), thus indicating that this represents a hotspot. By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R133C (300005.0001) and R294X were associated with the mildest phenotype. Autism, Susceptibility to, X-Linked 3 Carney et al. (2003) identified this mutation in a female with classic autism disorder (AUTSX3; 300496) who had most of the diagnostic features of RTT. Analysis for skewed X chromosome inactivation in blood leukocytes showed that she had a 29% pattern. (less)
Pathogenic (Mar 11, 2008)	no assertion criteria provided Method: literature only	RETT SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032825.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 10854091‚ 18332345‚ 12770674 Comment on evidence: Rett Syndrome De Bona et al. (2000) identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated … (more) Rett Syndrome De Bona et al. (2000) identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated patients with Rett syndrome (RTT; 312750), thus indicating that this represents a hotspot. By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R133C (300005.0001) and R294X were associated with the mildest phenotype. Autism, Susceptibility to, X-Linked 3 Carney et al. (2003) identified this mutation in a female with classic autism disorder (AUTSX3; 300496) who had most of the diagnostic features of RTT. Analysis for skewed X chromosome inactivation in blood leukocytes showed that she had a 29% pattern. (less)
Pathogenic (Sep 26, 2019)	no assertion criteria provided Method: clinical testing	Rett syndrome Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001133059.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929887.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951861.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Dec 05, 2013)	no assertion criteria provided Method: curation	Rett syndrome Affected status: yes Allele origin: unknown, de novo, germline	RettBASE Accession: SCV000222441.1 First in ClinVar: Apr 24, 2015 Last updated: Apr 24, 2015	Publications: PubMed (50): PubMed: 10745042 10814718 10814719 10854091 10944854 10991688 10991689 11055898 11106359 11214906 11241840 11245712 11269512 11309679 11313756 11402105 11462237 11469283 11524741 11738864 11738865 11738885 11913567 11960578 12081725 12111643 12180070 12325033 12567420 12770674 12966523 15057977 15173251 15389714 15526954 15737703 16473305 16672765 17089071 17236109 17387578 17420824 17986102 19189931 19652677 19722030 20031356 22476991 22525432 23810759 Observation 1: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Atypical Observation 2: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: not stated Comment on evidence: Rett syndrome - classical Observation 3: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 4: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 5: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 6: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 7: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 8: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 9: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 10: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 11: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 12: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 13: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 14: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 15: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 16: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Classical Observation 17: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Classical Observation 18: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Classical Observation 19: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Classical Observation 20: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 21: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 22: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 23: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 24: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 25: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 26: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Forme fruste Observation 27: Number of individuals with the variant: 1 Family history: No Sex: male Tissue: blood Comment on evidence: Rett syndrome - male variant Observation 28: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 29: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 30: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 31: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 32: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Not certain Observation 33: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 34: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 35: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 36: Number of individuals with the variant: 1 Family history: Yes Sex: female Tissue: Not known Comment on evidence: Rett syndrome - Not certain Observation 37: Number of individuals with the variant: 1 Family history: Yes Sex: female Tissue: Not known Comment on evidence: Rett syndrome - Not certain Observation 38: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 39: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 40: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 41: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 42: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 43: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 44: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - Not certain Observation 45: Number of individuals with the variant: 1 Family history: No Tissue: blood Comment on evidence: Rett syndrome - Not certain Observation 46: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 47: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 48: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 49: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 50: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Not certain Observation 51: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Not certain Observation 52: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Not certain Observation 53: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 54: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 55: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 56: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 57: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 58: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 59: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 60: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 61: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 62: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 63: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Atypical Observation 64: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Atypical Observation 65: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 66: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Classical Observation 67: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Classical Observation 68: Number of individuals with the variant: 1 Sex: female Tissue: lymphocytes Comment on evidence: Rett syndrome - Classical Observation 69: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 70: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - Atypical Observation 71: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - Atypical Observation 72: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Not certain Observation 73: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Not certain Observation 74: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 75: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood or fibroblasts Comment on evidence: Rett syndrome - classical Observation 76: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood or fibroblasts Comment on evidence: Rett syndrome - classical Observation 77: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood or fibroblasts Comment on evidence: Rett syndrome - classical Observation 78: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 79: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 80: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 81: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 82: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 83: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 84: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: NK Comment on evidence: Rett syndrome - classical Observation 85: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: not known Comment on evidence: Rett syndrome - classical Observation 86: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: not known Comment on evidence: Rett syndrome - classical Observation 87: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: not known Comment on evidence: Rett syndrome - classical Observation 88: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 89: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - Not certain Observation 90: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 91: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 92: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 93: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 94: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 95: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 96: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 97: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 98: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 99: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 100: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 101: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 102: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 103: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 104: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 105: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 106: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 107: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 108: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 109: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 110: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 111: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 112: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 113: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 114: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Atypical Observation 115: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 116: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical Observation 117: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 118: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 119: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 120: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 121: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 122: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 123: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 124: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 125: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 126: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 127: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 128: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 129: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Atypical Observation 130: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 131: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - preserved speech Observation 132: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - classical Observation 133: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - classical Observation 134: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - classical Observation 135: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - classical Observation 136: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 137: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 138: Number of individuals with the variant: 1 Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Classical Observation 139: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 140: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 141: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 142: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 143: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - Classical Observation 144: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: not stated Comment on evidence: Not Rett synd. - Rett-like Observation 145: Number of individuals with the variant: 1 Tissue: blood Comment on evidence: Rett syndrome - atypical Observation 146: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Not certain Observation 147: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 148: Number of individuals with the variant: 1 Tissue: blood Comment on evidence: Rett syndrome - Not certain Observation 149: Number of individuals with the variant: 1 Tissue: blood Comment on evidence: Rett syndrome - Not certain Observation 150: Number of individuals with the variant: 1 Tissue: blood Comment on evidence: Rett syndrome - Not certain Observation 151: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 152: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 153: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 154: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 155: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 156: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 157: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 158: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 159: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 160: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 161: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 162: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - preserved speech Observation 163: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: NK Comment on evidence: Rett syndrome - classical Observation 164: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 165: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 166: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 167: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 168: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 169: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 170: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 171: Number of individuals with the variant: 1 Family history: No Tissue: Blood Comment on evidence: Rett syndrome - Not certain Observation 172: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 173: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 174: Number of individuals with the variant: 1 Sex: female Tissue: not known Comment on evidence: Rett syndrome - not certain Observation 175: Number of individuals with the variant: 1 Sex: female Tissue: not known Comment on evidence: Rett syndrome - not certain Observation 176: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: Blood Comment on evidence: Rett syndrome - atypical Observation 177: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 178: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 179: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 180: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 181: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 182: Number of individuals with the variant: 1 Sex: female Tissue: Blood or skin Comment on evidence: Rett syndrome - Classical Observation 183: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 184: Number of individuals with the variant: 1 Sex: female Tissue: blood Comment on evidence: Rett syndrome - not certain Observation 185: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - classical Observation 186: Number of individuals with the variant: 1 Sex: female Comment on evidence: Rett syndrome - classical Observation 187: Number of individuals with the variant: 1 Comment on evidence: Rett syndrome - Not certain Observation 188: Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Rett syndrome - classical Observation 189: Number of individuals with the variant: 1 Family history: No Sex: female Comment on evidence: Rett syndrome - Classical
Pathogenic (Dec 05, 2013)	no assertion criteria provided Method: curation	Austism susceptibility, X-linked Affected status: yes Allele origin: unknown	RettBASE Accession: SCV000188271.2 First in ClinVar: Aug 15, 2014 Last updated: Apr 22, 2015	Publications: PubMed (1) PubMed: 16473305 Number of individuals with the variant: 1 Family history: No Sex: female Tissue: blood Comment on evidence: Not Rett synd. - autism only
Pathogenic (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Rett syndrome Affected status: yes Allele origin: de novo	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427578.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Publications: PubMed (1) PubMed: 25741868
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744886.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (Jul 07, 2024)	no assertion criteria provided Method: clinical testing	MECP2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362598.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MECP2 c.880C>T variant is predicted to result in premature protein termination (p.Arg294). This variant has been reported in individuals with Rett syndrome (Milunsky et … (more) The MECP2 c.880C>T variant is predicted to result in premature protein termination (p.Arg294). This variant has been reported in individuals with Rett syndrome (Milunsky et al. 2001. PubMed ID: 11960578; Fukuda et al. 2005. PubMed ID: 15737703; LIMA et al. 2009. PubMed ID: 19722030; Psoni et al. 2012. PubMed ID: 21982064). Of note, this variant has also been reported in individuals with atypical Rett syndrome and has been associated with a slightly milder form of disease (Fukuda et al. 2005. PubMed ID: 15737703; Psoni et al. 2012. PubMed ID: 21982064). A transcription assay performed in Xenopus oocytes showed that this variant altered protein function (Yusufzai et al. 2000. PubMed ID: 11058114). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Comment:

The p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting).

Comment:

The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to RettBASE below and references therein, Cheadle 2000, Pidcock 2016, Wen 2017, Wang 2016). Additionally, the variant protein is reported to have lowered expression, to have slightly reduced stability, and to be unable to repress transcription (Wen 2017, Yusufzai 2000). The variant is reported in the ClinVar database (Variation ID: 11819). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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. Considering available information, this variant is classified as pathogenic. References: Link to RettBase variants: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic 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. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wen Z et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017 Aug 3;8:43. Wang T et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. Yusufzai TM and Wolffe AP. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.

Comment:

The c.880C>T;p.(Arg294*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11819; PMID: 31535341; 28465761; 26800272; 23270700; 16473305; 18332345; 11241840; 15737703; 19722030; 29046627) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history(PMID: 23810759) - PS2. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11058114; 26604147) - PS3_moderate. This variant is not present in population databases (rs61751362, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The stop gained p.R294* in MECP2 (NM_004992.3) has been reported multiple times in females affected with Rett syndrome and is also present in the Rett database (Boban et al; Wen Z et al). It has shown to promote apoptosis of identified neurons in vivo (Williams A et al). It has been submitted to the ClinVar database as Pathogenic. The p.R294* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant causes the premature termination of MECP2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with Rett syndrome (PMID: 11241840 (2001), 23270700 (2013), 31535341 (2020)). In addition, a functional study reported this variant resulted in a damaging effect on protein function (PMID: 11058114 (2000)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Comment:

Variant summary: The MECP2 c.880C>T (p.Arg294X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1079C>A/p.Ser360X)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87847 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional study proved mutant protein R294X with loss of function (Yusufzai_ 2000). Taken together, this variant is classified as pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11960578, 15737703, 19722030, 21982064). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11241840). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011819/ PMID: 10767337/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007); Observed in females with both classic and atypical Rett syndrome, often associated with a milder clinical presentation, and has been identified in a male with progressive microcephaly, developmental regression, and a movement disorder (RettBASE; Neul et al., 2008; Lundvall et al., 2006); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 193 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it is defective in promoting nucleosome-nucleosome bridging (Yusufzai et al., 2000; Nikitina et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11058114, 26604147, 10991688, 17660293, 23270700, 27159028, 27824329, 10767337, 27255190, 29321033, 28785396, 29421650, 29595472, 29056246, 16077729, 26175308, 17420824, 11738864, 18337588, 17236109, 18174548, 30693677, 30564305, 30536762, 31209962, 31535341, 32105570, 32472557, 32005694, 33994118, 12030010, 31130284, 31031587)

Comment:

This variant has been reported in the literature in numerous individuals with Rett syndrome, including males, and as de novo in at least 1 individual with autism spectrum disorder (ASD) (Selected publications: Cheadler 2000 PMID:10767337, Yamashita 2001 PMID:11738864, Jian 2005 PMID:16077729, Lundvall 2006 PMID:17236109, Stachon 2007 PMID:17420824, Wen 2017 PMID:28785396). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11819). Functional studies support that this variant will impact the protein, suggesting repression of transcription and instability (Yusufzai 2000 PMID:11058114). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or abnormal protein. Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However, the vast majority of pathogenic variants in this gene (including this variant) 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 PMID:16473305). In summary, this variant is classified as pathogenic.

Comment:

This variant is also known as c.880C>T (p.Arg294Ter) due to use of an alternate transcript. This nonsense variant found in exon 4 of 4 is predicted to result in truncation of the MeCP2 protein. This variant has been previously reported in individuals with MECP2-related disorders (PMID:16473305, 11241840, 15737703, 19722030, 11960578, 21982064). Functional studies have shown that the c.916C>T (p.Arg306Ter) variant destabilizes the MeCP2 protein and expression of the truncated protein in-vitro results in increased apoptosis levels (PMID: 11058114, 27442528, 28785396). The c.916C>T (p.Arg306Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.916C>T (p.Arg306Ter) variant is classified as Pathogenic.

Comment:

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 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 with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). 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 (PS3_supporting).

Comment:

This sequence change creates a premature translational stop signal (p.Arg294*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 193 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 individuals with Rett syndrome (PMID: 11241840, 15737703, 16473305, 17236109, 18332345, 19722030, 23270700). ClinVar contains an entry for this variant (Variation ID: 11819). 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, 26604147, 27442528, 28785396). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.880C>T (p.R294*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 880. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 294. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 38% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in many females with classic Rett syndrome. In addition, several studies show that this pathogenic variant is associated with a milder phenotype including, but not limited to: a later age at diagnosis (5-6 years of age), delayed onset of regression, later onset of stereotypical behaviors, more retention of words and hand function, and ambulatory ability (Cheadle, 2000; Fieremans, 2016; Pidcock, 2016; Wen, 2017; Colvin, 2004; Fehr, 2010). The p.R294* amino acid is located within the transcription repression domain, which normally binds methylated DNA in the context of chromatin, leading to long-term transcriptional repression (Hite, 2009). Functional analysis demonstrated that the p.R294* alteration retains DNA binding capabilities at levels comparable to those of the wild-type protein, but failed to repress DNA transcription (Yusufzai, 2000). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene, where both protein instability and increased cell death have been demonstrated (OMIM, PMID: 27442528). (N) 0104 - Mechanism of disease for this gene is dominant negative. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 4 of 4). (P) 0301 - Variant is absent from gnomAD. (P) 0601 - Variant affects at the well established (essential) functional C-terminal region (PMID: 27442528). (P) 0701 - Comparable variants also predicted to result in a truncated protein, have very strong previous evidence for pathogenicity in patients with Rett syndrome (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in multiple de novo individuals with Rett syndrome (Decipher, ClinVar). (P) 0905 - No published segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where both animal models and transfected cell lines demonstrated increased cell death (PMID: 27442528). (P) 1204 - De Novo Variant (Parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

The MECP2 c.880C>T variant is predicted to result in premature protein termination (p.Arg294*). This variant has been reported in individuals with Rett syndrome (Milunsky et al. 2001. PubMed ID: 11960578; Fukuda et al. 2005. PubMed ID: 15737703; LIMA et al. 2009. PubMed ID: 19722030; Psoni et al. 2012. PubMed ID: 21982064). Of note, this variant has also been reported in individuals with atypical Rett syndrome and has been associated with a slightly milder form of disease (Fukuda et al. 2005. PubMed ID: 15737703; Psoni et al. 2012. PubMed ID: 21982064). A transcription assay performed in Xenopus oocytes showed that this variant altered protein function (Yusufzai et al. 2000. PubMed ID: 11058114). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variant Profile of MECP2 Gene in Sri Lankan Patients with Rett Syndrome.	Hettiarachchi D	Journal of autism and developmental disorders	2020	PMID: 31535341
MeCP2 Deficiency in Neuroglia: New Progress in the Pathogenesis of Rett Syndrome.	Jin XR	Frontiers in molecular neuroscience	2017	PMID: 29046627
Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.	Wen Z	Molecular autism	2017	PMID: 28785396
Autonomic breathing abnormalities in Rett syndrome: caregiver perspectives in an international database study.	Mackay J	Journal of neurodevelopmental disorders	2017	PMID: 28465761
Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations.	Williams AA	PloS one	2016	PMID: 27442528
Determinants of sleep disturbances in Rett syndrome: Novel findings in relation to genotype.	Boban S	American journal of medical genetics. Part A	2016	PMID: 27255190
Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern.	Fieremans N	Human mutation	2016	PMID: 27159028
Validating the Rett Syndrome Gross Motor Scale.	Downs J	PloS one	2016	PMID: 26800272
Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes.	Delépine C	Human molecular genetics	2016	PMID: 26604147
Functional outcomes in Rett syndrome.	Pidcock FS	Brain & development	2016	PMID: 26175308
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males).	Maortua H	The Journal of molecular diagnostics : JMD	2013	PMID: 23810759
Detection of rarely identified multiple mutations in MECP2 gene do not contribute to enhanced severity in Rett syndrome.	Chapleau CA	American journal of medical genetics. Part A	2013	PMID: 23696494
Pubertal trajectory in females with Rett syndrome: a population-based study.	Knight O	Brain & development	2013	PMID: 23270700
Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis.	Todorov T	Mutation research	2012	PMID: 22525432
Genetic and epileptic features in Rett syndrome.	Kim HJ	Yonsei medical journal	2012	PMID: 22476991
MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders.	Psoni S	Brain & development	2012	PMID: 21982064
Atypical presentations and specific genotypes are associated with a delay in diagnosis in females with Rett syndrome.	Fehr S	American journal of medical genetics. Part A	2010	PMID: 20815036
Identification and characterization of novel sequence variations in MECP2 gene in Rett syndrome patients.	Monnerat LS	Brain & development	2010	PMID: 20031356
Genotype-phenotype correlation in Brazillian Rett syndrome patients.	Lima FT	Arquivos de neuro-psiquiatria	2009	PMID: 19722030
Spectrum of MECP2 mutations in New Zealand Rett syndrome patients.	Raizis AM	The New Zealand medical journal	2009	PMID: 19652677
Recent advances in MeCP2 structure and function.	Hite KC	Biochemistry and cell biology = Biochimie et biologie cellulaire	2009	PMID: 19234536
Methyl-CpG-binding protein 2 (MECP2) gene mutations in an Italian sample of patients with pervasive developmental disorder and mental retardation.	Parmeggiani A	Journal of child neurology	2009	PMID: 19189931
Investigating genotype-phenotype relationships in Rett syndrome using an international data set.	Bebbington A	Neurology	2008	PMID: 18332345
MECP2 mutations in Serbian Rett syndrome patients.	Djarmati A	Acta neurologica Scandinavica	2007	PMID: 17986102
Rett syndrome: clinical and molecular characterization of two Brazilian patients.	Stachon A	Arquivos de neuro-psiquiatria	2007	PMID: 17420824
Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms.	Zahorakova D	Journal of human genetics	2007	PMID: 17387578
MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.	Li MR	Journal of human genetics	2007	PMID: 17089071
Male Rett phenotypes in T158M and R294X MeCP2-mutations.	Lundvall M	Neuropediatrics	2006	PMID: 17236109
Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome.	Kim IJ	Experimental & molecular medicine	2006	PMID: 16672765
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update.	Philippe C	European journal of medical genetics	2006	PMID: 16473305
Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms.	Fukuda T	Brain & development	2005	PMID: 15737703
Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype.	Chae JH	Journal of child neurology	2004	PMID: 15526954
Mutation analysis of MECP2 and determination of the X-inactivation pattern in Hungarian Rett syndrome patients.	Kárteszi J	American journal of medical genetics. Part A	2004	PMID: 15389714
Screening of MECP2 coding sequence in patients with phenotypes of decreasing likelihood for Rett syndrome: a cohort of 171 cases.	Kammoun F	Journal of medical genetics	2004	PMID: 15173251
Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.	Schanen C	American journal of medical genetics. Part A	2004	PMID: 15057977
Refining the phenotype of common mutations in Rett syndrome.	Colvin L	Journal of medical genetics	2004	PMID: 14729826
Rett syndrome in adolescent and adult females: clinical and molecular genetic findings.	Smeets E	American journal of medical genetics. Part A	2003	PMID: 12966523
Identification of MeCP2 mutations in a series of females with autistic disorder.	Carney RM	Pediatric neurology	2003	PMID: 12770674
Mutation analysis of the MECP2 gene in patients with Rett syndrome.	Conforti FL	American journal of medical genetics. Part A	2003	PMID: 12567420
MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome.	Yaron Y	Human mutation	2002	PMID: 12325033
Spectrum of MECP2 mutations in Rett syndrome.	Bienvenu T	Genetic testing	2002	PMID: 12180070
MECP2 gene mutation analysis in Chinese patients with Rett syndrome.	Pan H	European journal of human genetics : EJHG	2002	PMID: 12111643
MECP2 mutations in Swedish Rett syndrome clusters.	Xiang F	Clinical genetics	2002	PMID: 12081725
Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome.	Chae JH	Journal of child neurology	2002	PMID: 11913567
Mutation analysis in Rett syndrome.	Milunsky JM	Genetic testing	2001	PMID: 11960578
Rett syndrome in Spain: mutation analysis and clinical correlations.	Monrós E	Brain & development	2001	PMID: 11738885
The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome.	Ishii T	Brain & development	2001	PMID: 11738865
Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in Rett patients with preserved speech.	Yamashita Y	Brain & development	2001	PMID: 11738864
Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation.	Yamada Y	Human mutation	2001	PMID: 11524741
MECP2 mutation screening in Swedish classical Rett syndrome females.	Erlandson A	European child & adolescent psychiatry	2001	PMID: 11469283
DHPLC analysis of the MECP2 gene in Italian Rett patients.	Nicolao P	Human mutation	2001	PMID: 11462237
MeCP2 mutations in children with and without the phenotype of Rett syndrome.	Hoffbuhr K	Neurology	2001	PMID: 11402105
MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.	Nielsen JB	European journal of human genetics : EJHG	2001	PMID: 11313756
MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.	Trappe R	American journal of human genetics	2001	PMID: 11309679
Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.	Vacca M	Journal of molecular medicine (Berlin, Germany)	2001	PMID: 11269512
MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.	Auranen M	Neurology	2001	PMID: 11245712
Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions.	Laccone F	Human mutation	2001	PMID: 11241840
A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.	Bourdon V	Human genetics	2001	PMID: 11214906
Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome.	Lam CW	Journal of medical genetics	2000	PMID: 11106359
Functional consequences of Rett syndrome mutations on human MeCP2.	Yusufzai TM	Nucleic acids research	2000	PMID: 11058114
Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.	Buyse IM	American journal of human genetics	2000	PMID: 11055898
Mutations in the MECP2 gene in a cohort of girls with Rett syndrome.	Hampson K	Journal of medical genetics	2000	PMID: 10991689
Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome.	Obata K	Journal of medical genetics	2000	PMID: 10991688
Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.	Amano K	Journal of human genetics	2000	PMID: 10944854
Preserved speech variant is allelic of classic Rett syndrome.	De Bona C	European journal of human genetics : EJHG	2000	PMID: 10854091
MECP2 mutations account for most cases of typical forms of Rett syndrome.	Bienvenu T	Human molecular genetics	2000	PMID: 10814719
Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.	Huppke P	Human molecular genetics	2000	PMID: 10814718
Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.	Cheadle JP	Human molecular genetics	2000	PMID: 10767337
Mutation screening in Rett syndrome patients.	Xiang F	Journal of medical genetics	2000	PMID: 10745042
[Comparative and experimental studies on various prosthesis cleaners. 1. Testing of mechanical cleans power and the action on prosthesis materials].	Ehmer D	Stomatologie der DDR	1975	PMID: 1105898
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4f9581c4-3218-4790-a62d-dae2c9df284f	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ede88874-946c-4213-9897-197e908f3c6d	-	-	-	-
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Text-mined citations for rs61751362 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter)

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Citations for germline classification of this variant

Text-mined citations for rs61751362 ...