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.941C>T (p.Pro314Leu)

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Curation History
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CA270574

143738 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 5440749b-7ac5-4fba-8a4a-70847f234b72

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NM_001110792.2:c.941C>T

NM_001110792.2(MECP2):c.941C>T (p.Pro314Leu)

NC_000023.11:g.154030923G>A

CM000685.2:g.154030923G>A

NC_000023.10:g.153296374G>A

CM000685.1:g.153296374G>A

NC_000023.9:g.152949568G>A

NG_007107.2:g.111205C>T

NG_007107.3:g.111181C>T

ENST00000303391.11:c.905C>T

ENST00000453960.7:c.941C>T

ENST00000637917.1:n.79C>T

ENST00000303391.10:c.905C>T

ENST00000407218.5:c.*277C>T

ENST00000453960.6:c.941C>T

ENST00000619732.4:c.905C>T

ENST00000622433.4:c.891C>T

ENST00000628176.2:c.*277C>T

NM_001110792.1:c.941C>T

NM_001316337.1:c.626C>T

NM_004992.3:c.905C>T

NM_001316337.2:c.626C>T

NM_001369391.2:c.626C>T

NM_001369392.2:c.626C>T

NM_001369393.2:c.626C>T

NM_001369394.1:c.626C>T

NM_001369394.2:c.626C>T

NM_001386137.1:c.236C>T

NM_001386138.1:c.236C>T

NM_001386139.1:c.236C>T

NM_004992.4:c.905C>T

Pathogenic

PS4 PP4 PP3 PM2_Supporting PM6_Strong PM5 PM1

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.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in at least 4 of these individuals (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong). The p.(Pro302Leu) variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5). In summary, the c.905C>T p.(Pro302Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PP3, PP4, PM2_supporting).

PS4

The p.Pro302Leu variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4).

PP4

The p.Pro302Leu variant in MECP2 has been reported in individuals with a clinical phenotype suggestive of Rett syndrome (PMID PMID: 10767337, 30377382, 23696494, 11313756, 16473305) (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.Pro302Leu variant in MECP2 is absent from gnomAD (PM2_supporting).

PM6_Strong

The p.Pro302Leu variant in MECP2 has been reported in at least 4 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome and severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong).

PM5

Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5).

PM1

The p.Pro302Leu variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1).

Curation History

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