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NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys) AND Rett syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 28, 2023
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:
RCV001800452.5

Allele description [Variation Report for NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys)]

NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys)

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.379C>T (p.Arg127Cys)
Other names:
p.R115C:CGC>TGC; NM_001110792.2(MECP2):c.379C>T; p.Arg127Cys
HGVS:
  • NC_000023.11:g.154032241G>A
  • NG_007107.3:g.109863C>T
  • NM_001110792.2:c.379C>TMANE SELECT
  • NM_001316337.2:c.64C>T
  • NM_001369391.2:c.64C>T
  • NM_001369392.2:c.64C>T
  • NM_001369393.2:c.64C>T
  • NM_001369394.2:c.64C>T
  • NM_001386137.1:c.-218C>T
  • NM_001386138.1:c.-218C>T
  • NM_001386139.1:c.-218C>T
  • NM_004992.4:c.343C>T
  • NP_001104262.1:p.Arg127Cys
  • NP_001303266.1:p.Arg22Cys
  • NP_001356320.1:p.Arg22Cys
  • NP_001356321.1:p.Arg22Cys
  • NP_001356322.1:p.Arg22Cys
  • NP_001356323.1:p.Arg22Cys
  • NP_004983.1:p.Arg115Cys
  • NP_004983.1:p.Arg115Cys
  • LRG_764t1:c.379C>T
  • LRG_764t2:c.343C>T
  • AJ132917.1:c.343C>T
  • LRG_764:g.109863C>T
  • LRG_764p1:p.Arg127Cys
  • LRG_764p2:p.Arg115Cys
  • NC_000023.10:g.153297692G>A
  • NC_000023.10:g.153297692G>A
  • NG_007107.2:g.109887C>T
  • NM_004992.3:c.343C>T
Protein change:
R115C
Links:
dbSNP: rs267608388
NCBI 1000 Genomes Browser:
rs267608388
Molecular consequence:
  • NM_001386137.1:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001386138.1:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001386139.1:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001110792.2:c.379C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001316337.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369391.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369392.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369393.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369394.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004992.4:c.343C>T - 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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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002047366ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RettAS ACMG Specifications MECP2 V3.0.0)		Uncertain significance
(Aug 28, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002047366.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Arg115Cys (NM_004992.4) in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533). The p.Arg115Cys variant (NM_004992.4) occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115Cys variant (NM_004992.4) in MECP2 is absent from gnomAD (PM2_supporting). The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2). In summary, the p.Arg115Cys variant in MECP2 (NM_004992.4) is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, BS2).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024