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.505T>A (p.Phe169Ile)

CA274628

143585 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 948c8bb3-c0a5-4e88-a2fd-7ed9cad5a0dd
Approved on: 2022-10-11
Published on: 2022-12-02

HGVS expressions

NM_001110792.2:c.505T>A
NM_001110792.2(MECP2):c.505T>A (p.Phe169Ile)
NC_000023.11:g.154031359A>T
CM000685.2:g.154031359A>T
NC_000023.10:g.153296810A>T
CM000685.1:g.153296810A>T
NC_000023.9:g.152950004A>T
NG_007107.2:g.110769T>A
NG_007107.3:g.110745T>A
ENST00000303391.11:c.469T>A
ENST00000453960.7:c.505T>A
ENST00000637917.1:n.65+37T>A
ENST00000303391.10:c.469T>A
ENST00000407218.5:c.468+37T>A
ENST00000453960.6:c.505T>A
ENST00000486506.5:n.2817T>A
ENST00000611468.1:c.457T>A
ENST00000619732.4:c.469T>A
ENST00000622433.4:c.457T>A
ENST00000628176.2:c.432+37T>A
NM_001110792.1:c.505T>A
NM_001316337.1:c.190T>A
NM_004992.3:c.469T>A
NM_001316337.2:c.190T>A
NM_001369391.2:c.190T>A
NM_001369392.2:c.190T>A
NM_001369393.2:c.190T>A
NM_001369394.1:c.190T>A
NM_001369394.2:c.190T>A
NM_001386137.1:c.-129+37T>A
NM_001386138.1:c.-129+37T>A
NM_001386139.1:c.-129+37T>A
NM_004992.4:c.469T>A
More

Likely Pathogenic

Met criteria codes 7
PS3_Supporting PS4_Moderate PP3 PM1 PM5 PM6 PM2_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.Phe157Ile variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with a clinical phenotype suggestive of MECP2-related conditions (PMID 16832102) (PM6). The p.Phe157Ile variant in MECP2 has been observed in 2 additional individuals with Rett syndrome (RettBASE) (PS4_moderate). The p.Phe157Ile variant occurs in the well-characterized methyl-DNA binding functional domain of MECP2 (PM1). A pathogenic missense variant (p.Phe157Leu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 19722030, 16225173, 22476991, 30536762, 15675358, ClinVar) (PM5). The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting). A MECP2 chromatin binding assay has shown that this variant impacts protein function (PMID 27929079) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Phe157Ile variant in MECP2 is classified as Likely Pathogenic for MECP2-related conditions based on the ACMG/AMP criteria (PM1, PM5, PM6, PS4_moderate, PM2_supporting, PS3_supporting, PP3 ).
Met criteria codes
PS3_Supporting
A MECP2 chromatin binding assay has shown that this variant impacts protein function (PMID 27929079) (PS3_supporting).
PS4_Moderate
The p.Phe157Ile variant in MECP2 (NM_004992.3) has been observed in 3 individuals with MECP2-related conditions (PMID 16832102, RettBASE) (PS4_moderate).
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
PM1
The p.Phe157Ile variant occurs in the well-characterized methyl-DNA binding functional domain of MECP2 (PM1).
PM5
A pathogenic missense variant (p.Phe157Leu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 19722030, 16225173, 22476991, 30536762, 15675358, ClinVar) (PM5).
PM6
The p.Phe157Ile variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with a clinical phenotype suggestive of MECP2-related conditions (PMID 16832102) (PM6).
PM2_Supporting
The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting).
Curation History
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