NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys) AND Rett syndrome

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Mar 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000133095.23

Allele description [Variation Report for NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)]

NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)

Gene:

MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)

Other names:

NM_001110792.2(MECP2):c.437C>G; p.Ser146Cys

HGVS:

NC_000023.11:g.154031427G>C
NG_007107.3:g.110677C>G
NM_001110792.2:c.437C>GMANE SELECT
NM_001316337.2:c.122C>G
NM_001369391.2:c.122C>G
NM_001369392.2:c.122C>G
NM_001369393.2:c.122C>G
NM_001369394.2:c.122C>G
NM_001386137.1:c.-160C>G
NM_001386138.1:c.-160C>G
NM_001386139.1:c.-160C>G
NM_004992.4:c.401C>G
NP_001104262.1:p.Ser146Cys
NP_001303266.1:p.Ser41Cys
NP_001356320.1:p.Ser41Cys
NP_001356321.1:p.Ser41Cys
NP_001356322.1:p.Ser41Cys
NP_001356323.1:p.Ser41Cys
NP_004983.1:p.Ser134Cys
NP_004983.1:p.Ser134Cys
LRG_764t1:c.437C>G
LRG_764t2:c.401C>G
AJ132917.1:c.401C>G
LRG_764:g.110677C>G
LRG_764p1:p.Ser146Cys
LRG_764p2:p.Ser134Cys
NC_000023.10:g.153296878G>C
NG_007107.2:g.110701C>G
NM_004992.3:c.401C>G
NM_004992.4:c.401C>G
P51608:p.Ser134Cys

Protein change:

S134C

Links:

UniProtKB: P51608#VAR_010278; dbSNP: rs61748390

NCBI 1000 Genomes Browser:

rs61748390

Molecular consequence:

NM_001386137.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.401C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Rett syndrome (RTT)
Synonyms:: Autism, dementia, ataxia, and loss of purposeful hand use; Rett's disorder
Identifiers:: MONDO: MONDO:0010726; MedGen: C0035372; Orphanet: 3095; Orphanet: 778; OMIM: 312750

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188085	RettBASE	no assertion criteria provided	Pathogenic (Nov 1, 2011)	maternal, de novo, unknown	curation	PubMed (10) [See all records that cite these PMIDs] 10814718, 10991688, 11269512, 11738864, 11738883, 15737703, 16182490, 17089071, 17387578, 21160487
SCV000247967	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000537175	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 7, 2015)	de novo	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15737703, 11738883, 2460487, 10814718, 17089071, 10991688, 16182490, 11269512, 17387578, 25741868
SCV001362253	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 11, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17089071, 21831886, 17387578, 18337588, 17142618, 21178819, 23696494, 26418480 Citation Link,
SCV001427579	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	no assertion criteria provided	Pathogenic (Jan 1, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002053932	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV002107099	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588, 10767337, 23696494, 22182064, 25741868
SCV002506805	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Jun 11, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10767337, 12661945, 21228398, 26418480, 31164858, 21831886 Citation Link,
SCV004100763	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004808969	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 8, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	1	not provided	curation
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	yes	9	not provided	not provided	9	No	clinical testing, curation
not provided	de novo	yes	6	not provided	not provided	5	No	clinical testing, research, curation
not provided	maternal	yes	2	not provided	not provided	2	Yes	curation
not provided	unknown	no	1	not provided	not provided	1	Yes	curation

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms.

Fukuda T, Yamashita Y, Nagamitsu S, Miyamoto K, Jin JJ, Ohmori I, Ohtsuka Y, Kuwajima K, Endo S, Iwai T, Yamagata H, Tabara Y, Miki T, Matsuishi T, Kondo I.

Brain Dev. 2005 Apr;27(3):211-7.

PubMed [citation]

PMID:: 15737703

See all PubMed Citations (26)

Details of each submission

From RettBASE, SCV000188085.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (10)
2	not provided	1	not provided	Yes	curation	PubMed (10)
3	not provided	1	not provided	Yes	curation	PubMed (10)
4	not provided	1	not provided	No	curation	PubMed (10)
5	not provided	1	not provided	No	curation	PubMed (10)
6	not provided	1	not provided	No	curation	PubMed (10)
7	not provided	1	not provided	No	curation	PubMed (10)
8	not provided	1	not provided	No	curation	PubMed (10)
9	not provided	1	not provided	not provided	curation	PubMed (10)
10	not provided	1	not provided	No	curation	PubMed (10)
11	not provided	1	not provided	No	curation	PubMed (10)
12	not provided	1	not provided	not provided	curation	PubMed (10)
13	not provided	1	not provided	not provided	curation	PubMed (10)
14	not provided	1	not provided	not provided	curation	PubMed (10)
15	not provided	1	not provided	No	curation	PubMed (10)
16	not provided	1	not provided	Yes	curation	PubMed (10)
17	not provided	1	not provided	No	curation	PubMed (10)
18	not provided	1	not provided	No	curation	PubMed (10)

Description

"Not known"

PubMed [ID: 16182490]

"Not Rett synd. - Unaffected family member"

PubMed [ID: 16182490]

Rett syndrome - Atypical

Rett syndrome - classical

Rett syndrome - Classical

Rett syndrome - not certain

"Rett syndrome - Classical"

PubMed [ID: 10814718]

"Rett syndrome - Not certain"

PubMed [ID: 10991688]

"Rett syndrome - classical"

PubMed [ID: 11269512]

"Rett syndrome - Classical"

PubMed [ID: 11269512]

"Rett syndrome - not certain"

PubMed [ID: 11738864]

"Rett syndrome - Classical"

PubMed [ID: 11738883]

"Rett syndrome - Classical"

PubMed [ID: 15737703]

"Rett syndrome - Not certain"

PubMed [ID: 16182490]

"Rett syndrome - Male variant"

PubMed [ID: 17089071]

"Rett syndrome - not certain"

PubMed [ID: 17387578]

"Rett syndrome - Classical"

PubMed [ID: 21160487]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	blood	not provided		1	not provided	not provided	not provided
2	unknown	no	1	blood	not provided		1	not provided	not provided	not provided
3	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided
4	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
6	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
8	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided
9	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
10	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
11	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
12	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
13	unknown	yes	1	Blood or skin	not provided		1	not provided	not provided	not provided
14	unknown	yes	1	Blood or skin	not provided		1	not provided	not provided	not provided
15	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided
16	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided
17	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
18	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000247967.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000537175.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362253.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: MECP2 c.401C>G (p.Ser134Cys) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181626 control chromosomes (gnomAD). c.401C>G has been reported in the literature in multiple individuals affected with Rett Syndrome, in some cases as a de novo mutation (example: Chapleau_2013, Li_2007, Neul_2008, Petel-Galil_2006, Roende_2011, Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant has been reported to reduce the ability of the MECP2 protein to bind and cluster heterochromatin and was shown to cause destabilization of the methyl-CpG-binding domain of the protein (example: Agarwal_2011, Kucukkal_2015). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV001427579.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002053932.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DASA, SCV002107099.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

The c.401C>G;p.(Ser134Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 143562; PMID: 10814718; PMID: 11738864; PMID: 17089071; PMID: 12655490; PMID: 21160487; PMID: 11738883; PMID: 18337588) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (MBD) - PM1. This variant is not present in population databases (rs61748390- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 143563) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 10767337; 23696494; 22182064) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002506805.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is a known pathogenic variant and has been reported in multiple unrelated individuals affected with Rett syndrome [PMID:10767337; PMID:12661945; PMID:21228398; PMID:26418480; PMID: 31164858]. The variant has been reported as Pathogenic/Likely Pathogenic in ClinVar by multiple independent laboratories [Variation ID: 143562]. The variant is absent from gnomAD(v3) suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools [CADD score = 27.7, REVEL score = 0.988). Functional studies have suggested that the c.401C>G (p.Ser134Cys) variant destabilizes the MBD domain of the MECP2 protein and reduces its ability to bind and cluster heterochromatin [PMID: 26418480; PMID: 21831886]. Based on the available evidence, the heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is reported as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004100763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP,PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Population Genomics, CPG, SCV004808969.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

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 at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 17089071, 10991688, 11269512) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 17407838, 17387578, 11269512, 17089071, 11738864, 10991688, 10814718, ClinVar Variation ID: 143562) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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