Variant: NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys)

CA294544

143541 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

UUID: 3f058a05-d354-4c3c-ab58-d9f040ab9270

Approved on: 2023-08-28

Published on: 2023-09-15

HGVS expressions

NM_001110792.2:c.379C>T
NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys)
NC_000023.11:g.154032241G>A
CM000685.2:g.154032241G>A
NC_000023.10:g.153297692G>A
CM000685.1:g.153297692G>A
NC_000023.9:g.152950886G>A
NG_007107.2:g.109887C>T
NG_007107.3:g.109863C>T
ENST00000303391.11:c.343C>T
ENST00000453960.7:c.379C>T
ENST00000303391.10:c.343C>T
ENST00000369957.5:c.*397C>T
ENST00000407218.5:c.379C>T
ENST00000453960.6:c.379C>T
ENST00000486506.5:n.2691C>T
ENST00000611468.1:c.331C>T
ENST00000619732.4:c.343C>T
ENST00000622433.4:c.331C>T
ENST00000628176.2:c.343C>T
NM_001110792.1:c.379C>T
NM_001316337.1:c.64C>T
NM_004992.3:c.343C>T
NM_001316337.2:c.64C>T
NM_001369391.2:c.64C>T
NM_001369392.2:c.64C>T
NM_001369393.2:c.64C>T
NM_001369394.1:c.64C>T
NM_001369394.2:c.64C>T
NM_001386137.1:c.-218C>T
NM_001386138.1:c.-218C>T
NM_001386139.1:c.-218C>T
NM_004992.4:c.343C>T

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PM1 BS2

• Not Met criteria codes: PP4 PM6

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Arg115Cys (NM_004992.4) in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533). The p.Arg115Cys variant (NM_004992.4) occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115Cys variant (NM_004992.4) in MECP2 is absent from gnomAD (PM2_supporting). The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2). In summary, the p.Arg115Cys variant in MECP2 (NM_004992.4) is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, BS2).

Met criteria codes

• 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.Arg127Cys variant in MECP2 is absent from gnomAD (PM2_supporting).
• PM1: The p.Arg115Cys variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1).
• BS2: The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2).

Not Met criteria codes

• PP4: The p.Arg115Cys variant in MECP2 has been identified in the hemizygous state in two males with seizures (internal database, GeneDx).
• PM6: The p.Arg115Cys in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533).