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_004992.3(MECP2):c.454C>G (p.Pro152Ala)

CA121717

11844 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 692d4de8-21e1-4102-8ec2-4da4b8d9c892

HGVS expressions

NM_004992.3:c.454C>G

NM_004992.3(MECP2):c.454C>G (p.Pro152Ala)

ENST00000303391.11:c.454C>G

ENST00000453960.7:c.490C>G

ENST00000637917.1:n.65+22C>G

ENST00000303391.10:c.454C>G

ENST00000369957.5:c.*508C>G

ENST00000407218.5:c.468+22C>G

ENST00000453960.6:c.490C>G

ENST00000486506.5:n.2802C>G

ENST00000611468.1:c.442C>G

ENST00000619732.4:c.454C>G

ENST00000622433.4:c.442C>G

ENST00000628176.2:c.432+22C>G

NM_001110792.1:c.490C>G

NM_001316337.1:c.175C>G

NM_001110792.2:c.490C>G

NM_001316337.2:c.175C>G

NM_001369391.2:c.175C>G

NM_001369392.2:c.175C>G

NM_001369393.2:c.175C>G

NM_001369394.1:c.175C>G

NM_001369394.2:c.175C>G

NM_001386137.1:c.-129+22C>G

NM_001386138.1:c.-129+22C>G

NM_001386139.1:c.-129+22C>G

NM_004992.4:c.454C>G

NC_000023.11:g.154031374G>C

CM000685.2:g.154031374G>C

NC_000023.10:g.153296825G>C

CM000685.1:g.153296825G>C

NC_000023.9:g.152950019G>C

NG_007107.2:g.110754C>G

NG_007107.3:g.110730C>G

Likely Pathogenic

PM5 PM1 PP1_Moderate PS3_Supporting PP3

PM2

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

Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database) (PP1_Moderate). The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro152Ala variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS3_supporting, PP1_moderate, PM1, PM5, PP3).

PM5

A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337)

PM1

The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2

PP1_Moderate

The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database)

PS3_Supporting

Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701)

PP3

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

PM2

The variant (p.Pro152Ala) is found at extremely low frequency in gnomAD AT 0.001% and absent in ExAC

Approved on: 2021-03-26

Published on: 2021-05-17

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