The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4).
ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
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.961C>T (p.Arg321Trp)
Variation ID: 143749 Accession: VCV000143749.69
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 154030903 (GRCh38) [ NCBI UCSC ] X: 153296354 (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 Oct 20, 2024 Jul 28, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001110792.2:c.961C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Arg321Trp missense NM_004992.4:c.925C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Arg309Trp missense NM_001316337.2:c.646C>T NP_001303266.1:p.Arg216Trp missense NM_001369391.2:c.646C>T NP_001356320.1:p.Arg216Trp missense NM_001369392.2:c.646C>T NP_001356321.1:p.Arg216Trp missense NM_001369393.2:c.646C>T NP_001356322.1:p.Arg216Trp missense NM_001369394.2:c.646C>T NP_001356323.1:p.Arg216Trp missense NM_001386137.1:c.256C>T NP_001373066.1:p.Arg86Trp missense NM_001386138.1:c.256C>T NP_001373067.1:p.Arg86Trp missense NM_001386139.1:c.256C>T NP_001373068.1:p.Arg86Trp missense NC_000023.11:g.154030903G>A NC_000023.10:g.153296354G>A NG_007107.3:g.111201C>T LRG_764:g.111201C>T LRG_764t1:c.961C>T LRG_764p1:p.Arg321Trp LRG_764t2:c.925C>T LRG_764p2:p.Arg309Trp AJ132917.1:c.925C>T - Protein change
- R309W, R321W, R216W, R86W
- Other names
-
p.R309W:CGG>TGG
NM_001110792.2(MECP2):c.961C>T
p.Arg321Trp
- Canonical SPDI
- NC_000023.11:154030902:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 25, 2021 | RCV000133293.43 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Dec 5, 2013 | RCV000170240.4 | |
| Pathogenic (13) |
reviewed by expert panel
|
Jul 28, 2022 | RCV000170241.31 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2017 | RCV000169947.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 14, 2015 | RCV000624661.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 5, 2019 | RCV000851523.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 30, 2023 | RCV001049007.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 14, 2024 | RCV003984819.3 |
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
(Jul 28, 2022)
|
reviewed by expert panel
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: SCV002569941.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
Comment:
The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, … (more)
The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4). (less)
|
|
|
Pathogenic
(Jun 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248007.2
First in ClinVar: Oct 05, 2015 Last updated: Nov 10, 2017 |
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: case-control
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
Biochemistry Laboratory of CDMU, Chengde Medical University
Accession: SCV000899194.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
|
|
|
Pathogenic
(Apr 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
Affected status: yes
Allele origin:
de novo
|
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV000994583.1
First in ClinVar: Sep 28, 2019 Last updated: Sep 28, 2019 |
|
|
|
Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000807252.2
First in ClinVar: May 30, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in … (more)
This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly (less)
|
|
|
Likely pathogenic
(Dec 14, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741171.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Peripheral neuropathy (present) , Macrocephalus (present) , Obesity (present) , Asthma (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Diabetes insipidus … (more)
Seizures (present) , Peripheral neuropathy (present) , Macrocephalus (present) , Obesity (present) , Asthma (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Diabetes insipidus (present) , Depressivity (present) , Sleep disturbance (present) , Round face (present) , Midface retrusion (present) , Depressed nasal bridge (present) , Stellate iris (present) , Skin rash (present) , Neurodevelopmental delay (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000190988.15
First in ClinVar: Nov 01, 2014 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227) (less)
|
|
|
Pathogenic
(Jun 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV003836688.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Mar 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003932164.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
PS2_Very Strong, PS4, PM2, PP3
|
|
|
Pathogenic
(Apr 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368505.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS2_VSTR,PS4,PM2_SUP,PM5_SUP,PP3
Clinical Features:
Moderate global developmental delay (present) , Parietal cortical atrophy (present) , EEG with spike-wave complexes (present) , Intellectual disability, moderate (present) , Renal insufficiency (present) … (more)
Moderate global developmental delay (present) , Parietal cortical atrophy (present) , EEG with spike-wave complexes (present) , Intellectual disability, moderate (present) , Renal insufficiency (present) , Generalized atonic seizure (present) (less)
Sex: female
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000575669.32
First in ClinVar: Jul 24, 2016 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 4
|
|
|
Likely pathogenic
(Apr 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: unknown
Allele origin:
de novo
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000809080.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
|
|
|
Likely pathogenic
(Oct 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000343620.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251808.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446400.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present)
|
|
|
Likely pathogenic
(Oct 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
maternal
|
Laboratoire Génétique Moléculaire, CHRU TOURS
Accession: SCV001760747.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Clinical Features:
Neurodevelopmental delay (present) , Macrocephaly (present) , Intrauterine growth retardation (present) , Jaundice (present) , Hypotonia (present) , Triangular-shaped open mouth (present) , Downslanted palpebral … (more)
Neurodevelopmental delay (present) , Macrocephaly (present) , Intrauterine growth retardation (present) , Jaundice (present) , Hypotonia (present) , Triangular-shaped open mouth (present) , Downslanted palpebral fissures (present) , Epicanthus (present) (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
inherited
|
Suma Genomics
Accession: SCV001837627.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
|
|
|
Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045783.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Seizure (present)
|
|
|
Pathogenic
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe neonatal-onset encephalopathy with microcephaly
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001213039.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
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: SCV004801240.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Mar 13, 2024)
|
criteria provided, single submitter
Method: curation
|
Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Centre for Population Genomics, CPG
Accession: SCV004808989.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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 … (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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). (PMID: 31178897, 26936630) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 26936630, 21178819, 30536762, 21160487, 28089766, 37361459, 31178897 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). (less)
|
|
|
Pathogenic
(Aug 01, 2019)
|
no assertion criteria provided
Method: research
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Section for Clinical Neurogenetics, University of Tübingen
Accession: SCV001156091.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
|
|
Uncertain significance
(Dec 05, 2013)
|
no assertion criteria provided
Method: curation
|
Mental retardation, X-linked, syndromic 13
Affected status: yes
Allele origin:
de novo,
unknown
|
RettBASE
Accession: SCV000188302.2
First in ClinVar: Aug 17, 2014 Last updated: Apr 22, 2015 |
Observation 1:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: not stated
Comment on evidence:
Not Rett synd. - intellectual disability
Observation 2:
Number of individuals with the variant: 1
Family history: No
Sex: male
Tissue: blood
Comment on evidence:
Not Rett synd. - psychomotor delay and absence of speech
|
|
|
Uncertain significance
(Dec 05, 2013)
|
no assertion criteria provided
Method: curation
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
RettBASE
Accession: SCV000222572.1
First in ClinVar: Apr 24, 2015 Last updated: Apr 24, 2015 |
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - atypical
|
|
|
Uncertain significance
(Dec 05, 2013)
|
no assertion criteria provided
Method: curation
|
Austism susceptibility, X-linked
Affected status: yes
Allele origin:
de novo
|
RettBASE
Accession: SCV000222571.1
First in ClinVar: Apr 22, 2015 Last updated: Apr 22, 2015 |
Number of individuals with the variant: 1
Sex: female
Tissue: blood, lymphoblastoid cell lin
Comment on evidence:
Not Rett synd. - autism spectrum disorder
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Rett syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000998928.2
First in ClinVar: Nov 17, 2019 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227)
Comment:
PS2_Very Strong, PS4, PM2, PP3
Comment:
Criteria applied: PS2_VSTR,PS4,PM2_SUP,PM5_SUP,PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been 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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). (PMID: 31178897, 26936630) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 26936630, 21178819, 30536762, 21160487, 28089766, 37361459, 31178897 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
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:
The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4).
Comment:
This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227)
Comment:
PS2_Very Strong, PS4, PM2, PP3
Comment:
Criteria applied: PS2_VSTR,PS4,PM2_SUP,PM5_SUP,PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been 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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). (PMID: 31178897, 26936630) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 26936630, 21178819, 30536762, 21160487, 28089766, 37361459, 31178897 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. | Hengel H | European journal of human genetics : EJHG | 2020 | PMID: 32214227 |
| The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. | Neul JL | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2019 | PMID: 30536762 |
| Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. | Staněk D | Orphanet journal of rare diseases | 2018 | PMID: 29720203 |
| The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. | Schönewolf-Greulich B | Clinical genetics | 2016 | PMID: 26936630 |
| 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 |
| Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations. | Hadzsiev K | Journal of human genetics | 2011 | PMID: 21160487 |
| Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. | Piton A | Molecular psychiatry | 2011 | PMID: 20479760 |
| Recent advances in MeCP2 structure and function. | Hite KC | Biochemistry and cell biology = Biochimie et biologie cellulaire | 2009 | PMID: 19234536 |
| Low significance of MECP2 mutations as a cause of mental retardation in Brazilian males. | Campos M Jr | Brain & development | 2007 | PMID: 17084570 |
| MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. | Nan X | Cell | 1997 | PMID: 9038338 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0dd97332-47d7-4c58-a315-4099a29f30ae | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/431d1239-3305-42a4-967d-adae00522f20 | - | - | - | - |
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Text-mined citations for rs61751444 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.