Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_001110792.2(MECP2):c.784C>T (p.Arg262Cys)

CA205183

211466 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 42d1d263-dfac-4cab-832f-a8ddefada4fb
Approved on: 2023-12-06
Published on: 2023-12-08

HGVS expressions

NM_001110792.2:c.784C>T
NM_001110792.2(MECP2):c.784C>T (p.Arg262Cys)
NC_000023.11:g.154031080G>A
CM000685.2:g.154031080G>A
NC_000023.10:g.153296531G>A
CM000685.1:g.153296531G>A
NC_000023.9:g.152949725G>A
NG_007107.2:g.111048C>T
NG_007107.3:g.111024C>T
ENST00000303391.11:c.748C>T
ENST00000453960.7:c.784C>T
ENST00000637917.1:c.66-144C>T
ENST00000303391.10:c.748C>T
ENST00000407218.5:c.*120C>T
ENST00000453960.6:c.784C>T
ENST00000619732.4:c.748C>T
ENST00000622433.4:c.736C>T
ENST00000628176.2:c.*120C>T
NM_001110792.1:c.784C>T
NM_001316337.1:c.469C>T
NM_004992.3:c.748C>T
NM_001316337.2:c.469C>T
NM_001369391.2:c.469C>T
NM_001369392.2:c.469C>T
NM_001369393.2:c.469C>T
NM_001369394.1:c.469C>T
NM_001369394.2:c.469C>T
NM_001386137.1:c.79C>T
NM_001386138.1:c.79C>T
NM_001386139.1:c.79C>T
NM_004992.4:c.748C>T
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Likely Benign

Met criteria codes 1
BS2
Not Met criteria codes 6
PS4 PP3 PM5 PM1 BS1 BP4

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 c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2).
Met criteria codes
BS2
The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data).
Not Met criteria codes
PS4
The p.(Arg250Cys) variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency.
PP3
Computational prediction analysis tools are inconclusive for this variant (criteria not met).
PM5
Alternative missense variants (p.(Arg250Gly) and p.(Arg250His)) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au).
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The c.748C>T p.(Arg250Cys) variant in MECP2 (NM_004992.3) is present in 1 male and 4 female individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria).
BP4
Computational prediction analysis tools are inconclusive for this variant (criteria not met).
Curation History
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