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

CA270574

143738 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

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

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

• Met criteria codes: PM6_Strong PM2_Supporting PS4 PP4 PP3 PM5 PM1

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

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).

Met criteria codes

• 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).
• PM2_Supporting: The p.Pro302Leu variant in MECP2 is absent from gnomAD (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).
• 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).

Approved on: 2022-06-30

Published on: 2022-06-30