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]
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Variant: NM_001110792.2(MECP2):c.434G>T (p.Arg145Leu)

CA270390

143560 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 65ae8c8f-de06-4f4f-b4b2-72936e46dca4

HGVS expressions

NM_001110792.2:c.434G>T
NM_001110792.2(MECP2):c.434G>T (p.Arg145Leu)
NC_000023.11:g.154031430C>A
CM000685.2:g.154031430C>A
NC_000023.10:g.153296881C>A
CM000685.1:g.153296881C>A
NC_000023.9:g.152950075C>A
NG_007107.2:g.110698G>T
NG_007107.3:g.110674G>T
ENST00000303391.11:c.398G>T
ENST00000453960.7:c.434G>T
ENST00000637917.1:n.31G>T
ENST00000303391.10:c.398G>T
ENST00000369957.5:c.*452G>T
ENST00000407218.5:c.434G>T
ENST00000453960.6:c.434G>T
ENST00000486506.5:n.2746G>T
ENST00000611468.1:c.386G>T
ENST00000619732.4:c.398G>T
ENST00000622433.4:c.386G>T
ENST00000628176.2:c.398G>T
NM_001110792.1:c.434G>T
NM_001316337.1:c.119G>T
NM_004992.3:c.398G>T
NM_001316337.2:c.119G>T
NM_001369391.2:c.119G>T
NM_001369392.2:c.119G>T
NM_001369393.2:c.119G>T
NM_001369394.1:c.119G>T
NM_001369394.2:c.119G>T
NM_001386137.1:c.-163G>T
NM_001386138.1:c.-163G>T
NM_001386139.1:c.-163G>T
NM_004992.4:c.398G>T

Pathogenic

Met criteria codes 7
PS4_Supporting PP4 PP3 PM5_Strong PM6 PM2_Supporting PS3_Supporting

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.Arg133Leu variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome (PMID 10854091) (PM6). The p.Arg133Leu variant has been observed in at least 1 other individual with classic Rett syndrome (PMID 19722030) (PS4_supporting, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 30569584, 23421866, 11738879, 26418480, 16473305, 22368975; ClinVar) (PM5_strong). The p.Arg133Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays have shown that this variant impacts protein function (PMID 27929079, 22923521) (PS3_supporting). In summary, the p.Arg133Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS3_supporting, PS4_supporting, PM2_supporting, PP3 + PP4).
Met criteria codes
PS4_Supporting
The p.Arg133Leu variant has been observed in at least 1 other individual with classic Rett syndrome (PMIDs 19722030) (PS4_supporting).
PP4
The p.Arg133Leu variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 19722030) (PP4).
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
PM5_Strong
Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 30569584, 23421866, 11738879, 26418480, 16473305, 22368975; ClinVar) (PM5_strong).
PM6
The p.Arg133Leu variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome (PMID 10854091) (PM6).
PM2_Supporting
The p.Arg133Leu variant in MECP2 is absent from gnomAD (PM2_supporting).
PS3_Supporting
MECP2 chromatin binding assays have shown that this variant impacts protein function (PMID 27929079, 22923521) (PS3_supporting).
Approved on: 2022-10-11
Published on: 2022-12-02
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