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]

Link to SEPIO compliant JSON-LD document

Variant: NM_004992.3(MECP2):c.806delG (p.Gly269Alafs)

CA199475

95202 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 1e897fde-76a7-45dc-8f7f-6e1191668335

Approved on: 2021-03-09

Published on: 2021-05-07

HGVS expressions

NM_004992.3:c.806delG

NM_004992.3:c.806del

NM_004992.3(MECP2):c.806delG (p.Gly269Alafs)

ENST00000303391.11:c.806del

ENST00000453960.7:c.842del

ENST00000637917.1:n.66-86del

ENST00000303391.10:c.806del

ENST00000407218.5:c.*178del

ENST00000453960.6:c.842del

ENST00000619732.4:c.806del

ENST00000622433.4:c.794del

ENST00000628176.2:c.*178del

NM_001110792.1:c.842del

NM_001316337.1:c.527del

NM_001110792.2:c.842del

NM_001316337.2:c.527del

NM_001369391.2:c.527del

NM_001369392.2:c.527del

NM_001369393.2:c.527del

NM_001369394.1:c.527del

NM_001369394.2:c.527del

NM_001386137.1:c.137del

NM_001386138.1:c.137del

NM_001386139.1:c.137del

NM_004992.4:c.806del

NC_000023.11:g.154031025del

CM000685.2:g.154031025del

NC_000023.10:g.153296476del

CM000685.1:g.153296476del

NC_000023.9:g.152949670del

NG_007107.2:g.111106del

NG_007107.3:g.111082del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PS2_Very Strong PM2_Supporting

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.Gly269Alafs*20 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). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting).

PVS1

Met- Null variant (frame-shift) affecting gene MECP2, which is a known mechanism of disease, PMID: 12481990

PS2_Very Strong

≥2 independent occurrences of De novo (both maternity and paternity confirmed) in patients with the Rett syndrome and no family history,( PMID 26984561,10854091)

PM2_Supporting

Met- variant is absent in gnomAD

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