Variant: NM_001110792.2(MECP2):c.1244dup (p.Pro415_Glu416insTer)

CA10558465

429893 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

UUID: 2975ab3b-e66c-4632-81d1-b55b76117bf7

HGVS expressions

NM_001110792.2:c.1244dup
NM_001110792.2(MECP2):c.1244dup (p.Pro415_Glu416insTer)
NC_000023.11:g.154030625dup
CM000685.2:g.154030625dup
NC_000023.10:g.153296076dup
CM000685.1:g.153296076dup
NC_000023.9:g.152949270dup
NG_007107.2:g.111508dup
NG_007107.3:g.111484dup
ENST00000303391.11:c.1208dup
ENST00000453960.7:c.1244dup
ENST00000303391.10:c.1208dup
ENST00000407218.5:c.*580dup
ENST00000453960.6:c.1244dup
ENST00000619732.4:c.1208dup
ENST00000628176.2:c.*580dup
NM_001110792.1:c.1244dup
NM_001316337.1:c.929dup
NM_004992.3:c.1208dup
NM_001316337.2:c.929dup
NM_001369391.2:c.929dup
NM_001369392.2:c.929dup
NM_001369393.2:c.929dup
NM_001369394.1:c.929dup
NM_001369394.2:c.929dup
NM_001386137.1:c.539dup
NM_001386138.1:c.539dup
NM_001386139.1:c.539dup
NM_004992.4:c.1208dup

Uncertain Significance

• Met criteria codes: PM6_Supporting BS1 PVS1

• Not Met criteria codes: PS4 BA1 PM2

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Glu404Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu404Ter variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with seizures (PMID 29655203) (PM6_Supporting). The allele frequency of the p.Glu416Ter variant in MECP2 is 0.01173% in East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). In summary, the p.Glu404Ter variant in MECP2 is classified as variant of uncertain significance based on the ACMG/AMP criteria (BS1, PVS1, PM6_Supporting).

Met criteria codes

• PM6_Supporting: The p.Glu404Ter variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with seizures (PMID 29655203).
• BS1: The allele frequency of the p.Glu404Ter variant in MECP2 (NM_004992.4) is 0.01173% in East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions.
• PVS1: The p.Glu404Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-12-06

Published on: 2023-12-08