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]
  • See Evidence submitted by expert panel for details.

Variant: NM_001110792.2(MECP2):c.434G>A (p.Arg145His)

CA274538

143559 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 0fb2669b-a028-460e-a61d-84f544baf3a5
Approved on: 2021-10-26
Published on: 2021-12-27

HGVS expressions

NM_001110792.2:c.434G>A
NM_001110792.2(MECP2):c.434G>A (p.Arg145His)
NC_000023.11:g.154031430C>T
CM000685.2:g.154031430C>T
NC_000023.10:g.153296881C>T
CM000685.1:g.153296881C>T
NC_000023.9:g.152950075C>T
NG_007107.2:g.110698G>A
NG_007107.3:g.110674G>A
ENST00000303391.11:c.398G>A
ENST00000453960.7:c.434G>A
ENST00000637917.1:n.31G>A
ENST00000303391.10:c.398G>A
ENST00000369957.5:c.*452G>A
ENST00000407218.5:c.434G>A
ENST00000453960.6:c.434G>A
ENST00000486506.5:n.2746G>A
ENST00000611468.1:c.386G>A
ENST00000619732.4:c.398G>A
ENST00000622433.4:c.386G>A
ENST00000628176.2:c.398G>A
NM_001110792.1:c.434G>A
NM_001316337.1:c.119G>A
NM_004992.3:c.398G>A
NM_001316337.2:c.119G>A
NM_001369391.2:c.119G>A
NM_001369392.2:c.119G>A
NM_001369393.2:c.119G>A
NM_001369394.1:c.119G>A
NM_001369394.2:c.119G>A
NM_001386137.1:c.-163G>A
NM_001386138.1:c.-163G>A
NM_001386139.1:c.-163G>A
NM_004992.4:c.398G>A
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Pathogenic

Met criteria codes 8
PS3_Supporting PS4 PM2_Supporting PP3 PP4 PM1 PM5_Strong PS2_Very Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Arg133His variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 4 individuals with classic or atypical Rett syndrome (PMID 30569584, 17089071, 30945278) (PS2_very strong, PP4). The p.Arg133His variant has been observed in at least 3 other individuals with classic or atypical Rett syndrome (PMID 16473305, RettBASE) (PS4). Four additional pathogenic missense variants (p.Arg133Cys, p.Arg133Leu, p.Arg133Pro, p.Arg133Gly) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23421866, 11738879, 26418480, 16473305, 22368975, 10854091, 11960578, 12180070, Invitae - internal database) (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg133His variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM5_strong, PS3_supporting, PM2_supporting, PP3, PP4).
Met criteria codes
PS3_Supporting
Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting).
PS4
The p.Arg133His variant has been observed in at least 6 individuals with classic or atypical Rett syndrome (PMID 16473305, 30569584, 17089071, 30945278, RettBASE).
PM2_Supporting
The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting).
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
PP4
The p.Arg133His variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 30569584) (PP4).
PM1
The p.Arg133His variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of the MECP2 gene (PM1). Do not include this criteria as PM5_Strong is being used.
PM5_Strong
Four additional pathogenic missense variants (p.Arg133Cys, p.Arg133Leu, p.Arg133Pro, p.Arg133Gly) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23421866, 11738879, 26418480, 16473305, 22368975, 10854091, 11960578, 12180070, Invitae - internal database) (PM5_Strong).
PS2_Very Strong
The p.Arg133His variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 4 individuals with classic or atypical Rett syndrome (PMID 30569584, 17089071, 30945278) (PS2_very strong).
Curation History
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