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.491C>G (p.Pro164Arg)

Curation Version - 2.0
Curation History
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CA270424

143579 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 6d7ad90d-38fc-4fab-9db8-b6da72e59655

Approved on: 2021-10-26

Published on: 2024-09-09

HGVS expressions

NM_001110792.2:c.491C>G

NM_001110792.2(MECP2):c.491C>G (p.Pro164Arg)

NC_000023.11:g.154031373G>C

CM000685.2:g.154031373G>C

NC_000023.10:g.153296824G>C

CM000685.1:g.153296824G>C

NC_000023.9:g.152950018G>C

NG_007107.2:g.110755C>G

NG_007107.3:g.110731C>G

ENST00000303391.11:c.455C>G

ENST00000453960.7:c.491C>G

ENST00000637917.1:c.65+23C>G

ENST00000303391.10:c.455C>G

ENST00000369957.5:c.*509C>G

ENST00000407218.5:c.468+23C>G

ENST00000453960.6:c.491C>G

ENST00000486506.5:n.2803C>G

ENST00000611468.1:c.443C>G

ENST00000619732.4:c.455C>G

ENST00000622433.4:c.443C>G

ENST00000628176.2:c.432+23C>G

NM_001110792.1:c.491C>G

NM_001316337.1:c.176C>G

NM_004992.3:c.455C>G

NM_001316337.2:c.176C>G

NM_001369391.2:c.176C>G

NM_001369392.2:c.176C>G

NM_001369393.2:c.176C>G

NM_001369394.1:c.176C>G

NM_001369394.2:c.176C>G

NM_001386137.1:c.-129+23C>G

NM_001386138.1:c.-129+23C>G

NM_001386139.1:c.-129+23C>G

NM_004992.4:c.455C>G

Pathogenic

PS4 PP3 PP4 PM5 PM1 PM6_Very Strong PM2_Supporting PS3_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.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4).

PS4

The p.Pro152Arg variant has been observed in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, 10814718, 11241840, RettBASE) (PS4).

PP3

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

PP4

The p.Pro152Arg variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 10767337).

PM5

A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Grantham score Pro > Ala = 27 Grantham score Pro > Arg = 103

PM1

The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1).

PM6_Very Strong

The p.Pro152Arg variant in MECP2 has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID: 10767337, 10814718, 11241840) (PM6_very strong).

PM2_Supporting

The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting).

PS3_Supporting

Immunofluorescence assays have shown that this variant impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting).

Curation History

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