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Variant: NM_001110792.2(MECP2):c.437C>T (p.Ser146Phe)

CA270398

143563 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: cdabb0b8-00e6-4545-a4b7-f8005af1d548

HGVS expressions

NM_001110792.2:c.437C>T
NM_001110792.2(MECP2):c.437C>T (p.Ser146Phe)
NC_000023.11:g.154031427G>A
CM000685.2:g.154031427G>A
NC_000023.10:g.153296878G>A
CM000685.1:g.153296878G>A
NC_000023.9:g.152950072G>A
NG_007107.2:g.110701C>T
NG_007107.3:g.110677C>T
ENST00000303391.11:c.401C>T
ENST00000453960.7:c.437C>T
ENST00000637917.1:n.34C>T
ENST00000303391.10:c.401C>T
ENST00000369957.5:c.*455C>T
ENST00000407218.5:c.437C>T
ENST00000453960.6:c.437C>T
ENST00000486506.5:n.2749C>T
ENST00000611468.1:c.389C>T
ENST00000619732.4:c.401C>T
ENST00000622433.4:c.389C>T
ENST00000628176.2:c.401C>T
NM_001110792.1:c.437C>T
NM_001316337.1:c.122C>T
NM_004992.3:c.401C>T
NM_001316337.2:c.122C>T
NM_001369391.2:c.122C>T
NM_001369392.2:c.122C>T
NM_001369393.2:c.122C>T
NM_001369394.1:c.122C>T
NM_001369394.2:c.122C>T
NM_001386137.1:c.-160C>T
NM_001386138.1:c.-160C>T
NM_001386139.1:c.-160C>T
NM_004992.4:c.401C>T

Pathogenic

Met criteria codes 7
PS2 PP4 PP3 PM1 PM5 PM2_Supporting PS4_Moderate

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Ser134Phe variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 2 individuals with Rett syndrome (PMID 15737703, internal database - GeneDx) (PS2, PP4). The p.Ser134Phe variant has been observed in at least 1 other individual with Rett syndrome (PMID 21160487) (PS4_moderate). A pathogenic missense variant (p.Ser134Cys) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588, 10767337, 23696494, 22182064) (PM5). The p.Ser134Phe variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Ser134Phe variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ser134Phe variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PS4_moderate, PM1, PM5, PM2_supporting, PP3, PP4).
Met criteria codes
PS2
The p.Ser134Phe variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 2 individuals with Rett syndrome (PMID 15737703, internal database - GeneDx) (PS2).
PP4
The p.Ser134Phe variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15737703) (PP4).
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
PM1
The p.Ser134Phe variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1).
PM5
A pathogenic missense variant (p.Ser134Cys) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588, 10767337, 23696494, 22182064) (PM5).
PM2_Supporting
The p.Ser134Phe variant in MECP2 is absent from gnomAD (PM2_supporting).
PS4_Moderate
The p.Ser134Phe variant has been observed in at least 1 other individual with Rett syndrome (PMID 21160487) (PS4_moderate). [The variant has been seen in 3 affected individuals total, 2 de novo and documented under PM6_strong]
Approved on: 2021-10-26
Published on: 2021-12-27
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