Variant: NM_001110792.2(MECP2):c.1187C>T (p.Pro396Leu)

CA199482

36490 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

UUID: 38bf9f2d-64c8-4429-bc26-54f824404001

Approved on: 2023-03-27

Published on: 2023-03-31

HGVS expressions

NM_001110792.2:c.1187C>T
NM_001110792.2(MECP2):c.1187C>T (p.Pro396Leu)
NC_000023.11:g.154030677G>A
CM000685.2:g.154030677G>A
NC_000023.10:g.153296128G>A
CM000685.1:g.153296128G>A
NC_000023.9:g.152949322G>A
NG_007107.2:g.111451C>T
NG_007107.3:g.111427C>T
ENST00000303391.11:c.1151C>T
ENST00000453960.7:c.1187C>T
ENST00000303391.10:c.1151C>T
ENST00000407218.5:c.*523C>T
ENST00000453960.6:c.1187C>T
ENST00000619732.4:c.1151C>T
ENST00000628176.2:c.*523C>T
NM_001110792.1:c.1187C>T
NM_001316337.1:c.872C>T
NM_004992.3:c.1151C>T
NM_001316337.2:c.872C>T
NM_001369391.2:c.872C>T
NM_001369392.2:c.872C>T
NM_001369393.2:c.872C>T
NM_001369394.1:c.872C>T
NM_001369394.2:c.872C>T
NM_001386137.1:c.482C>T
NM_001386138.1:c.482C>T
NM_001386139.1:c.482C>T
NM_004992.4:c.1151C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BS2 BP5 PM6

• Not Met criteria codes: BS1 PS4

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Pro384Leu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with a neurological condition (PMID 22277191) (PM6). The p.Pro384Leu variant has been observed in 1 additional individual with intellectual disability (PMID 22277191) (not sufficient to meet PS4_supporting criteria). The p.Pro384Leu variant is observed in at least 8 unaffected individuals, most of whom are male (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro384Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The p.Pro384Leu variant in MECP2 is present in 2 female individual(s) in gnomAD (0.0012%) (not sufficient to meet BS1 criteria). In summary, this variant meets the criteria to be classified as Likely Benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: PM6, BS2, BP5 (ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2; date of approval 12/13/2021).

Met criteria codes

• BS2: The p.Pro384Leu variant is observed in at least 8 unaffected individuals, most of whom were male (internal database - GeneDx; internal database - Invitae) (BS2).
• BP5: The p.Pro384Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5).
• PM6: The p.Pro384Leu variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with a neurological condition (PMID 22277191) (PM6).

Not Met criteria codes

• BS1: Allele frequency in Latino subpopulation is 0.00007; does not meet BS1.
• PS4: The p.Pro384Leu variant has been observed in at least 1 individual with non-specific intellectual disability (PMID 22277191) (PS4_supporting not met).