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.1001C>T (p.Pro334Leu)

Curation Version - 1.0
Curation History
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CA270591

143754 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 4e3a5fc4-323d-4a09-8c72-f46d04b0eeb7

Approved on: 2022-07-05

Published on: 2022-09-06

HGVS expressions

NM_001110792.2:c.1001C>T

NM_001110792.2(MECP2):c.1001C>T (p.Pro334Leu)

NC_000023.11:g.154030863G>A

CM000685.2:g.154030863G>A

NC_000023.10:g.153296314G>A

CM000685.1:g.153296314G>A

NC_000023.9:g.152949508G>A

NG_007107.2:g.111265C>T

NG_007107.3:g.111241C>T

ENST00000303391.11:c.965C>T

ENST00000453960.7:c.1001C>T

ENST00000637917.1:n.139C>T

ENST00000303391.10:c.965C>T

ENST00000407218.5:c.*337C>T

ENST00000453960.6:c.1001C>T

ENST00000619732.4:c.965C>T

ENST00000622433.4:c.951C>T

ENST00000628176.2:c.*337C>T

NM_001110792.1:c.1001C>T

NM_001316337.1:c.686C>T

NM_004992.3:c.965C>T

NM_001316337.2:c.686C>T

NM_001369391.2:c.686C>T

NM_001369392.2:c.686C>T

NM_001369393.2:c.686C>T

NM_001369394.1:c.686C>T

NM_001369394.2:c.686C>T

NM_001386137.1:c.296C>T

NM_001386138.1:c.296C>T

NM_001386139.1:c.296C>T

NM_004992.4:c.965C>T

Pathogenic

PS4 PP4 PM5 PM6_Strong PM2_Supporting

PP3 PM1 BP4

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 c.965C>T p.(Pro322Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro322Leu) variant has been observed in at least 5 individuals with Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4, PP4), where it has been reported in as de novo occurrences (biological parentage unconfirmed) in at least 2 individuals (PMID 10814718, 11402105) (PM6_strong). Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5). In summary, the c.965C>T p.(Pro322Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PP4, PM5).

PS4

The p.Pro322Leu variant has been observed in at least 5 individuals with Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4).

PP4

The p.Pro322Leu variant in MECP2 has been reported in individuals with a clinical phenotype suggestive of Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PP4).

PM5

Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5).

PM6_Strong

The p.Pro322Leu variant in MECP2 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID 10814718, 11402105) (PM6_strong).

PM2_Supporting

The p.Pro322Leu variant in MECP2 is absent from gnomAD (PM2_supporting).

PP3

Computational prediction analysis tools are inconclusive for this variant.

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

Computational prediction analysis tools are inconclusive for this variant.

Curation History

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