Evidence Repository - Clinical Genome Resources

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>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

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

Pathogenic

PS3_Supporting PS2_Very Strong PS4 PP3 PP4 PM5_Strong PM2_Supporting PM1

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

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).

PS3_Supporting

Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting).

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).

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).

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).

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).

PM2_Supporting

The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting).

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.

Approved on: 2021-10-26

Published on: 2021-12-27

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