Variant: NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)

CA294622

156615 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

UUID: b50a48a5-25e8-47e2-a079-2c0c7b3b7de9

Approved on: 2022-07-21

Published on: 2022-09-06

HGVS expressions

NM_001110792.2:c.1165_1234del
NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)
NC_000023.11:g.154030635_154030704del
CM000685.2:g.154030635_154030704del
NC_000023.10:g.153296086_153296155del
CM000685.1:g.153296086_153296155del
NC_000023.9:g.152949280_152949349del
NG_007107.2:g.111429_111498del
NG_007107.3:g.111405_111474del
ENST00000303391.11:c.1129_1198del
ENST00000453960.7:c.1165_1234del
ENST00000303391.10:c.1129_1198del
ENST00000407218.5:c.*501_*570del
ENST00000453960.6:c.1165_1234del
ENST00000619732.4:c.1129_1198del
ENST00000628176.2:c.*501_*570del
NM_001110792.1:c.1165_1234del
NM_001316337.1:c.850_919del
NM_004992.3:c.1129_1198del
NM_001316337.2:c.850_919del
NM_001369391.2:c.850_919del
NM_001369392.2:c.850_919del
NM_001369393.2:c.850_919del
NM_001369394.1:c.850_919del
NM_001369394.2:c.850_919del
NM_001386137.1:c.460_529del
NM_001386138.1:c.460_529del
NM_001386139.1:c.460_529del
NM_004992.4:c.1129_1198del

Uncertain Significance

• Met criteria codes: PM2_Supporting BS2_Supporting PVS1 BP5

• Not Met criteria codes: PS4 PP4

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Lys377ProfsTer9) variant in MECP2 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.(Lys377ProfsTer9) variant has been reported in 1 individual with an epilepsy and neurodevelopmental disorder (PMID 29655203), and 1 individual with developmental delay and autism where it was inherited from a mother with a history of learning difficulties (ClinVar SCV000190972.2) (PS4_Supporting has not been applied as it is unclear whether these citations reflect two independent occurrences). The p.(Lys377ProfsTer9) variant has also been found in a patient with an alternate molecular basis of disease (PMID 29961512). This patient had early infantile epileptic encephalopathy, however did not meet the diagnostic criteria for either typical or atypical Rett. The p.(Lys377ProfsTer9) variant was found to be inherited from this patient's father, who was reported as having a history of seizures as a child and learning disability but was otherwise described as unaffected (BS2_Supporting). Furthermore, this patient was also found to be heterozygous for a de novo (biological parentage confirmed) GNAO1 missense variant that was deemed to be causative of this patient's clinical presentation (BP5). In summary, the c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PVS1, PM2_supporting, BP5, BS2_Supporting).

Met criteria codes

• PM2_Supporting: The p.(Lys377ProfsTer9) variant in MECP2 is absent from gnomAD (PM2_supporting).
• BS2_Supporting: The p.(Lys377ProfsTer9) variant has been observed in one patient's father who was reported as having a history of seizures as a child and learning disability but was otherwise described as unaffected (PMID: 29961512) (BS2_Supporting).
• PVS1: The p.(Lys377ProfsTer9) variant in MECP2 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).
• BP5: The p.(Lys377ProfsTer9) variant has been found in a patient with an alternate molecular basis of disease (PMID 29961512). This patient had early infantile epileptic encephalopathy however did not meet the diagnostic criteria for either typical or atypical Rett, and the p.(Lys377ProfsTer9) variant was found to be paternally inherited. Furthermore, this patient was also found to be heterozygous for a de novo (biological parentage unconfirmed) GNAO1 missense variant that was deemed to be causative of this patient's clinical presentation (BP5).

Not Met criteria codes

• PS4: The p.(Lys377ProfsTer9) variant has been reported in 1 individual with an epilepsy and neurodevelopmental disorder (PMID 29655203), and 1 individual with developmental delay and autism where it was inherited from a mother with a history of learning difficulties (ClinVar SCV000190972.2) (PS4_Supporting has not been applied as it is unclear whether these citations reflect two independent occurrences).