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NM_001110792.2(MECP2):c.368G>C (p.Arg123Thr) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 23, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003640345.2

Allele description [Variation Report for NM_001110792.2(MECP2):c.368G>C (p.Arg123Thr)]

NM_001110792.2(MECP2):c.368G>C (p.Arg123Thr)

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.368G>C (p.Arg123Thr)
HGVS:
  • NC_000023.11:g.154032252C>G
  • NG_007107.3:g.109852G>C
  • NM_001110792.2:c.368G>CMANE SELECT
  • NM_001316337.2:c.53G>C
  • NM_001369391.2:c.53G>C
  • NM_001369392.2:c.53G>C
  • NM_001369393.2:c.53G>C
  • NM_001369394.2:c.53G>C
  • NM_001386137.1:c.-229G>C
  • NM_001386138.1:c.-229G>C
  • NM_001386139.1:c.-229G>C
  • NM_004992.4:c.332G>C
  • NP_001104262.1:p.Arg123Thr
  • NP_001303266.1:p.Arg18Thr
  • NP_001356320.1:p.Arg18Thr
  • NP_001356321.1:p.Arg18Thr
  • NP_001356322.1:p.Arg18Thr
  • NP_001356323.1:p.Arg18Thr
  • NP_004983.1:p.Arg111Thr
  • LRG_764t1:c.368G>C
  • LRG_764t2:c.332G>C
  • LRG_764:g.109852G>C
  • LRG_764p1:p.Arg123Thr
  • LRG_764p2:p.Arg111Thr
  • NC_000023.10:g.153297703C>G
Protein change:
R111T
Molecular consequence:
  • NM_001386137.1:c.-229G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001386138.1:c.-229G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001386139.1:c.-229G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001110792.2:c.368G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001316337.2:c.53G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369391.2:c.53G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369392.2:c.53G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369393.2:c.53G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369394.2:c.53G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004992.4:c.332G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Severe neonatal-onset encephalopathy with microcephaly
Synonyms:
Encephalopathy, neonatal severe; Encephalopathy, neonatal severe, due to MECP2 mutations
Identifiers:
MONDO: MONDO:0010397; MedGen: C1968556; Orphanet: 209370; OMIM: 300673

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004460332Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Apr 23, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions.

Laccone F, Huppke P, Hanefeld F, Meins M.

Hum Mutat. 2001 Mar;17(3):183-90.

PubMed [citation]
PMID:
11241840

Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain.

Kudo S, Nomura Y, Segawa M, Fujita N, Nakao M, Schanen C, Tamura M.

J Med Genet. 2003 Jul;40(7):487-93.

PubMed [citation]
PMID:
12843318
PMCID:
PMC1735522
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004460332.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg111 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11241840, 12843318, 21831886). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. This variant has not been reported in the literature in individuals affected with MECP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 111 of the MECP2 protein (p.Arg111Thr).

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

Last Updated: Sep 29, 2024