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.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

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

Likely Pathogenic

PM2_Supporting PS3_Supporting PS4_Moderate PP3 PM6 PM1 PM5

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.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 ).

PM2_Supporting

The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting).

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).

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).

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).

Approved on: 2022-10-11

Published on: 2022-12-02

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