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.439A>G (p.Lys147Glu)

CA270401

143564 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 4cc0ea18-84f8-4a59-b14d-908303cbe14c

HGVS expressions

NM_001110792.2:c.439A>G

NM_001110792.2(MECP2):c.439A>G (p.Lys147Glu)

NC_000023.11:g.154031425T>C

CM000685.2:g.154031425T>C

NC_000023.10:g.153296876T>C

CM000685.1:g.153296876T>C

NC_000023.9:g.152950070T>C

NG_007107.2:g.110703A>G

NG_007107.3:g.110679A>G

ENST00000303391.11:c.403A>G

ENST00000453960.7:c.439A>G

ENST00000637917.1:n.36A>G

ENST00000303391.10:c.403A>G

ENST00000369957.5:c.*457A>G

ENST00000407218.5:c.439A>G

ENST00000453960.6:c.439A>G

ENST00000486506.5:n.2751A>G

ENST00000611468.1:c.391A>G

ENST00000619732.4:c.403A>G

ENST00000622433.4:c.391A>G

ENST00000628176.2:c.403A>G

NM_001110792.1:c.439A>G

NM_001316337.1:c.124A>G

NM_004992.3:c.403A>G

NM_001316337.2:c.124A>G

NM_001369391.2:c.124A>G

NM_001369392.2:c.124A>G

NM_001369393.2:c.124A>G

NM_001369394.1:c.124A>G

NM_001369394.2:c.124A>G

NM_001386137.1:c.-158A>G

NM_001386138.1:c.-158A>G

NM_001386139.1:c.-158A>G

NM_004992.4:c.403A>G

Pathogenic

PS3_Supporting PS4 PP4 PP3 PM2_Supporting PM1 PM6

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.Lys135Glu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 22182064) (PM6). The p.Lys135Glu variant has been observed in at least 6 other individuals with Rett syndrome (PMID 11241840, 22982301, 18842453, 16473305, 17387578) (PS4 and PP4). The p.Lys135Glu variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Lys135Glu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). In summary, the p.Lys135Glu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PS3_supporting, PP3, PP4).

PS3_Supporting

MECP2 chromatin binding assays and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting).

PS4

The p.Lys135Glu variant has been observed in at least 6 other individuals with Rett syndrome (PMID 11241840, 22982301, 18842453, 16473305) (PS4).

PP4

The p.Lys135Glu variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 17387578) (PP4).

PP3

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

PM2_Supporting

The p.Lys135Glu variant in MECP2 is absent from gnomAD (PM2_supporting).

PM1

The p.Lys135Glu variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1).

PM6

The p.Lys135Glu variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 22182064) (PM6).

Approved on: 2021-10-26

Published on: 2021-12-27

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