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.946A>G (p.Lys316Glu)

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CA270580

143742 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 347060fc-6dd1-4d69-88d1-853b6e7ea0ae

Approved on: 2022-10-11

Published on: 2022-12-02

HGVS expressions

NM_001110792.2:c.946A>G

NM_001110792.2(MECP2):c.946A>G (p.Lys316Glu)

NC_000023.11:g.154030918T>C

CM000685.2:g.154030918T>C

NC_000023.10:g.153296369T>C

CM000685.1:g.153296369T>C

NC_000023.9:g.152949563T>C

NG_007107.2:g.111210A>G

NG_007107.3:g.111186A>G

ENST00000303391.11:c.910A>G

ENST00000453960.7:c.946A>G

ENST00000637917.1:n.84A>G

ENST00000303391.10:c.910A>G

ENST00000407218.5:c.*282A>G

ENST00000453960.6:c.946A>G

ENST00000619732.4:c.910A>G

ENST00000622433.4:c.896A>G

ENST00000628176.2:c.*282A>G

NM_001110792.1:c.946A>G

NM_001316337.1:c.631A>G

NM_004992.3:c.910A>G

NM_001316337.2:c.631A>G

NM_001369391.2:c.631A>G

NM_001369392.2:c.631A>G

NM_001369393.2:c.631A>G

NM_001369394.1:c.631A>G

NM_001369394.2:c.631A>G

NM_001386137.1:c.241A>G

NM_001386138.1:c.241A>G

NM_001386139.1:c.241A>G

NM_004992.4:c.910A>G

Likely Pathogenic

PM5_Strong PS3_Supporting PM2_Supporting PS4_Supporting PP3

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.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_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.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3).

PM5_Strong

Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong).

PS3_Supporting

MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_supporting).

PM2_Supporting

The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting).

PS4_Supporting

The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting).

PP3

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

Curation History

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