Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001110792.2(MECP2):c.838C>T (p.Arg280Trp)

CA233007

143700 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: e2ce1abc-f6a3-4a8a-bed8-da079fa97496
Approved on: 2025-05-07
Published on: 2025-06-30

HGVS expressions

NM_001110792.2:c.838C>T
NM_001110792.2(MECP2):c.838C>T (p.Arg280Trp)
NC_000023.11:g.154031026G>A
CM000685.2:g.154031026G>A
NC_000023.10:g.153296477G>A
CM000685.1:g.153296477G>A
NC_000023.9:g.152949671G>A
NG_007107.2:g.111102C>T
NG_007107.3:g.111078C>T
ENST00000303391.11:c.802C>T
ENST00000453960.7:c.838C>T
ENST00000637917.1:c.66-90C>T
ENST00000303391.10:c.802C>T
ENST00000407218.5:c.*174C>T
ENST00000453960.6:c.838C>T
ENST00000619732.4:c.802C>T
ENST00000622433.4:c.790C>T
ENST00000628176.2:c.*174C>T
NM_001110792.1:c.838C>T
NM_001316337.1:c.523C>T
NM_004992.3:c.802C>T
NM_001316337.2:c.523C>T
NM_001369391.2:c.523C>T
NM_001369392.2:c.523C>T
NM_001369393.2:c.523C>T
NM_001369394.1:c.523C>T
NM_001369394.2:c.523C>T
NM_001386137.1:c.133C>T
NM_001386138.1:c.133C>T
NM_001386139.1:c.133C>T
NM_004992.4:c.802C>T
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Uncertain Significance

Met criteria codes 3
BS2 BP5 PP3
Not Met criteria codes 3
BS1 PP4 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 4.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The highest population minor allele frequency of the p.Arg268Trp variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002175 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Arg268Trp variant is observed in at least 2 unaffected individuals (PMID 12750821, LabCorp Genetics (formerly Invitae) and GeneDx internal databases) (BS2). The p.Arg268Trp variant is found in a patient with an alternate molecular basis of disease (PMID: 32340510) (BP5). The p.Arg268Trp variant in MECP2 has been reported in male individuals described to have x-linked intellectual disability (PMID: 12750821), in female individuals described to have Rett syndrome (PMID: 18842453), and in unaffected female and male individuals (PMID: 1275082, GeneDx internal data) (PP4_not met). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg268Trp variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, BP5, PP3). (MECP2 Specifications v.4.1; curation approved on [5/7/2025])
Met criteria codes
BS2
The p.Arg268Trp variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (PMID 12750821, Invitae and GeneDx internal databases).
BP5
The p.Arg268Trp variant in MECP2 (NM_004992.4) is found in a patient with an alternate molecular basis of disease (PMID: 32340510)
PP3
Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
Not Met criteria codes
BS1
The highest population minor allele frequency of the p.Arg268Trp variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002175 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria).
PP4
The p.Arg268Trp variant in MECP2 (NM_004992.4) has been reported in male individuals described to have x-linked intellectual disability (PMID: 12750821), in female individuals described to have Rett syndrome (PMID: 18842453), and in unaffected female and male individuals (PMID: 1275082, GeneDx internal data).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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