NM_001110792.2(MECP2):c.334C>G (p.Leu112Val) AND Rett syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 10, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000012608.29

Allele description [Variation Report for NM_001110792.2(MECP2):c.334C>G (p.Leu112Val)]

NM_001110792.2(MECP2):c.334C>G (p.Leu112Val)

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.334C>G (p.Leu112Val)

Other names:

NM_001110792.2(MECP2):c.334C>G; p.Leu112Val

HGVS:

NC_000023.11:g.154032286G>C
NG_007107.3:g.109818C>G
NM_001110792.2:c.334C>GMANE SELECT
NM_001316337.2:c.19C>G
NM_001369391.2:c.19C>G
NM_001369392.2:c.19C>G
NM_001369393.2:c.19C>G
NM_001369394.2:c.19C>G
NM_001386137.1:c.-263C>G
NM_001386138.1:c.-263C>G
NM_001386139.1:c.-263C>G
NM_004992.4:c.298C>G
NP_001104262.1:p.Leu112Val
NP_001303266.1:p.Leu7Val
NP_001356320.1:p.Leu7Val
NP_001356321.1:p.Leu7Val
NP_001356322.1:p.Leu7Val
NP_001356323.1:p.Leu7Val
NP_004983.1:p.Leu100Val
NP_004983.1:p.Leu100Val
LRG_764t1:c.334C>G
LRG_764t2:c.298C>G
AJ132917.1:c.298C>G
LRG_764:g.109818C>G
LRG_764p1:p.Leu112Val
LRG_764p2:p.Leu100Val
NC_000023.10:g.153297737G>C
NG_007107.2:g.109842C>G
NM_004992.3:c.298C>G
P51608:p.Leu100Val

Protein change:

L100V; LEU100VAL

Links:

UniProtKB: P51608#VAR_017462; OMIM: 300005.0027; dbSNP: rs28935168

NCBI 1000 Genomes Browser:

rs28935168

Molecular consequence:

NM_001386137.1:c.-263C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-263C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-263C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.334C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.19C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.19C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.19C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.19C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.19C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.298C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000032843	OMIM	no assertion criteria provided	Pathogenic (Oct 15, 2003)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11055898, 12966522
SCV000188042	RettBASE	no assertion criteria provided	Uncertain significance (Sep 27, 2012)	de novo, unknown	curation	PubMed (5) [See all records that cite these PMIDs] 11055898, 11913567, 12966522, 16672765, 22476991
SCV002540678	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Pathogenic (May 10, 2022)	germline	curation	Citation Link,
SCV004808979	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 13, 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	de novo	yes	1	not provided	not provided	1	No	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	5	not provided	not provided	5	No	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.

Buyse IM, Fang P, Hoon KT, Amir RE, Zoghbi HY, Roa BB.

Am J Hum Genet. 2000 Dec;67(6):1428-36. Epub 2000 Oct 30.

PubMed [citation]

PMID:: 11055898
PMCID:: PMC1287920

Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome.

Chae JH, Hwang YS, Kim KJ.

J Child Neurol. 2002 Jan;17(1):33-6.

PubMed [citation]

PMID:: 11913567

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000032843.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a patient with Rett syndrome (RTT; 312750), Buyse et al. (2000) identified a 298C-G change in the MECP2 gene, resulting in a leu100-to-val (L100V) substitution.

Hammer et al. (2003) reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo L100V mutation in the MECP2 gene. The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. The authors suggested that the patient illustrated the importance of allele dosage on phenotypic expression.

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

From RettBASE, SCV000188042.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (5)
2	not provided	1	not provided	No	curation	PubMed (5)
3	not provided	1	not provided	No	curation	PubMed (5)
4	not provided	1	not provided	not provided	curation	PubMed (5)
5	not provided	1	not provided	No	curation	PubMed (5)
6	not provided	1	not provided	No	curation	PubMed (5)

Description

Rett syndrome - Not certain

"Rett syndrome - Not certain"

PubMed [ID: 11055898]

"Rett syndrome - Classical"

PubMed [ID: 11913567]

"Rett syndrome - classical"

PubMed [ID: 12966522]

"Rett syndrome - atypical"

PubMed [ID: 16672765]

"Rett syndrome - not certain"

PubMed [ID: 22476991]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
5	de novo	yes	1	Blood	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540678.1

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

Description

The p.Leu100Val (NM_004992) variant has been observed in at least 5 other individuals with Rett Syndrome (PMID: 22476991, 16672765, 12966522, 11913567, 11055898, RettBASE) (PS4). The p.Leu100Val variant occurs in the well-characterized Methyl-DNA binding [MBD] functional domain of the MECP2 (PM1). The p.Leu100Val variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Leu100Val variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with mild atypical Rett syndrome (PMID: 12966522)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu100Val variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PP3).

#	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 for Population Genomics, CPG, SCV004808979.1

#	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: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 22476991, 16672765, 12966522, 11913567, 11055898, ClinVar Variation ID: 11835 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 12966522) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 22476991 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: Oct 20, 2024

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