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.507C>G (p.Phe169Leu)

CA270435

143589 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 6c97e782-e936-4540-94ee-46205d786176

HGVS expressions

NM_001110792.2:c.507C>G

NM_001110792.2(MECP2):c.507C>G (p.Phe169Leu)

NC_000023.11:g.154031357G>C

CM000685.2:g.154031357G>C

NC_000023.10:g.153296808G>C

CM000685.1:g.153296808G>C

NC_000023.9:g.152950002G>C

NG_007107.2:g.110771C>G

NG_007107.3:g.110747C>G

ENST00000303391.11:c.471C>G

ENST00000453960.7:c.507C>G

ENST00000637917.1:n.65+39C>G

ENST00000303391.10:c.471C>G

ENST00000407218.5:c.468+39C>G

ENST00000453960.6:c.507C>G

ENST00000486506.5:n.2819C>G

ENST00000611468.1:c.459C>G

ENST00000619732.4:c.471C>G

ENST00000622433.4:c.459C>G

ENST00000628176.2:c.432+39C>G

NM_001110792.1:c.507C>G

NM_001316337.1:c.192C>G

NM_004992.3:c.471C>G

NM_001316337.2:c.192C>G

NM_001369391.2:c.192C>G

NM_001369392.2:c.192C>G

NM_001369393.2:c.192C>G

NM_001369394.1:c.192C>G

NM_001369394.2:c.192C>G

NM_001386137.1:c.-129+39C>G

NM_001386138.1:c.-129+39C>G

NM_001386139.1:c.-129+39C>G

NM_004992.4:c.471C>G

Pathogenic

PS1 PP4 PP3 PM1 PM5 PM2_Supporting PS4_Moderate

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 c.471C>G (p.Phe157Leu) variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15675358) (PP4). The p.Phe157Leu variant in MECP2 has been observed in 2 additional individuals with MECP2-related conditions (PMID 30536762, RettBASE) (PS4_moderate). The p.Phe157Leu variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Phe169Leu variant in MECP2 is absent from gnomAD (PM2_supporting). The c.471C>A variant in the MECP2 gene results in a p.Phe157Leu change that is a previously established pathogenic variant (ClinVar, Invitae - internal database) (PS1). A pathogenic missense variant (p.Phe157Ile) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16832102, 27929079, RettBASE) (PM5). In summary, the c.471C>G (p.Phe157Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1 + PM1 + PM5 + PS4_moderate + PM2_supporting + PP3 + PP4).

PS1

The c.471C>A variant in MECP2 gene (NM_004992.3) results in a p.Phe157Leu change that is a previously established pathogenic variant (ClinVar, Invitae - internal database) (PS1).

PP4

The p.Phe157Leu variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15675358) (PP4).

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).

PM1

The p.Phe157Leu variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1).

PM5

A pathogenic missense variant (p.Phe157Ile) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16832102, 27929079, RettBASE) (PM5).

PM2_Supporting

The p.Phe169Leu variant in MECP2 is absent from gnomAD (PM2_supporting).

PS4_Moderate

The p.Phe157Leu variant has been observed in 3 individuals with MECP2-related conditions (PMID 15675358, 30536762, RettBASE) (PS4_moderate).

Approved on: 2022-10-11

Published on: 2022-12-02

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