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]

Variant: NM_001110792.2(MECP2):c.416C>T (p.Pro139Leu)

Curation Version - 1.0
Curation History
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CA270373

143552 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 2161318a-9364-40db-a371-c3dd56921992

Approved on: 2021-10-26

Published on: 2021-12-27

HGVS expressions

NM_001110792.2:c.416C>T

NM_001110792.2(MECP2):c.416C>T (p.Pro139Leu)

NC_000023.11:g.154031448G>A

CM000685.2:g.154031448G>A

NC_000023.10:g.153296899G>A

CM000685.1:g.153296899G>A

NC_000023.9:g.152950093G>A

NG_007107.2:g.110680C>T

NG_007107.3:g.110656C>T

ENST00000303391.11:c.380C>T

ENST00000453960.7:c.416C>T

ENST00000637917.1:n.13C>T

ENST00000303391.10:c.380C>T

ENST00000369957.5:c.*434C>T

ENST00000407218.5:c.416C>T

ENST00000453960.6:c.416C>T

ENST00000486506.5:n.2728C>T

ENST00000611468.1:c.368C>T

ENST00000619732.4:c.380C>T

ENST00000622433.4:c.368C>T

ENST00000628176.2:c.380C>T

NM_001110792.1:c.416C>T

NM_001316337.1:c.101C>T

NM_004992.3:c.380C>T

NM_001316337.2:c.101C>T

NM_001369391.2:c.101C>T

NM_001369392.2:c.101C>T

NM_001369393.2:c.101C>T

NM_001369394.1:c.101C>T

NM_001369394.2:c.101C>T

NM_001386137.1:c.-181C>T

NM_001386138.1:c.-181C>T

NM_001386139.1:c.-181C>T

NM_004992.4:c.380C>T

Pathogenic

PS4 PP4 PP3 PM6_Strong PM1 PM2_Supporting

PS3

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.Pro127Leu variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, 22182064) (PM6_strong, PP4). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID: 11245712, 16473305, 11960578, internal database - Invitae) (PS4). The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2 (PMID: 21326358, 23770565) (PM1). The p.Pro127Leu 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). In summary, the p.Pro127Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4, PM1, PM2_supporting, PP3, PP4).

PS4

The p.Pro127Leu variant has been observed in at least 4 other individuals with Rett syndrome (PMID: 11245712, 11960578, 16473305, internal database - Invitae).

PP4

The p.Pro127Leu variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 16225173).

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.

PM6_Strong

The p.Pro127Leu variant in MECP2 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, 22182064).

PM1

The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2.

PM2_Supporting

The p.Pro127Leu variant in MECP2 is absent from gnomAD.

PS3

Heterochromatin affinity was evaluated in GFP-MeCP2 fusion protein in murine cells and heterochromatin staining was indistinguishable from wild type. Transcriptional repressive activity was higher than wild type in one Drosophila luciferase assay (PMID: 12843318).

Curation History

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