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_001110792.1(MECP2):c.916C>T (p.Arg306Ter)

CA121700

11819 (ClinVar)

Gene: MECP2 (HGNC:4204)

Condition: Rett syndrome (MONDO:0010726)

Inheritance Mode: X-linked inheritance

UUID: ede88874-946c-4213-9897-197e908f3c6d

Approved on: 2021-03-26

Published on: 2021-05-17

HGVS expressions

NM_001110792.1(MECP2):c.916C>T (p.Arg306Ter)

NM_001110792.1:c.916C>T

NC_000023.11:g.154030948G>A

CM000685.2:g.154030948G>A

NC_000023.10:g.153296399G>A

CM000685.1:g.153296399G>A

NC_000023.9:g.152949593G>A

NG_007107.2:g.111180C>T

NG_007107.3:g.111156C>T

ENST00000303391.11:c.880C>T

ENST00000453960.7:c.916C>T

ENST00000637917.1:n.66-12C>T

ENST00000303391.10:c.880C>T

ENST00000407218.5:c.*252C>T

ENST00000453960.6:c.916C>T

ENST00000619732.4:c.880C>T

ENST00000622433.4:c.866C>T

ENST00000628176.2:c.*252C>T

NM_001316337.1:c.601C>T

NM_004992.3:c.880C>T

NM_001110792.2:c.916C>T

NM_001316337.2:c.601C>T

NM_001369391.2:c.601C>T

NM_001369392.2:c.601C>T

NM_001369393.2:c.601C>T

NM_001369394.1:c.601C>T

NM_001369394.2:c.601C>T

NM_001386137.1:c.211C>T

NM_001386138.1:c.211C>T

NM_001386139.1:c.211C>T

NM_004992.4:c.880C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

PS3_Supporting PS2_Very Strong PVS1 PM2_Supporting PS4

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.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting).

PS3_Supporting

The p.Arg294* variant in MECP2 failed to repress transcription in oocytes in the transcription assay and decreased levels of protein stability.

PS2_Very Strong

This variant has been observed confirmed de novo in over 2 affected individuals at GeneDx and in the literature.

PVS1

The variant p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism.

PM2_Supporting

The p.Arg306Ter variant in MECP2 is absent from gnomAD.

PS4

The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with RettSyndrome (15737703, 11960578, 19722030, 21982064, RettBASE)

Curation History

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