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]
  • Gene label mismatch: MECP2 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001110792.2(MECP2):c.604C>T (p.Arg202Cys)

CA294710

156667 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 5c42f539-b240-41c6-9a1a-8bcaf2d446f4
Approved on: 2025-02-28
Published on: 2025-03-26

HGVS expressions

NM_001110792.2:c.604C>T
NM_001110792.2(MECP2):c.604C>T (p.Arg202Cys)
NC_000023.11:g.154031260G>A
CM000685.2:g.154031260G>A
NC_000023.10:g.153296711G>A
CM000685.1:g.153296711G>A
NC_000023.9:g.152949905G>A
NG_007107.2:g.110868C>T
NG_007107.3:g.110844C>T
ENST00000303391.11:c.568C>T
ENST00000453960.7:c.604C>T
ENST00000637917.1:c.65+136C>T
ENST00000303391.10:c.568C>T
ENST00000407218.5:c.495C>T
ENST00000453960.6:c.604C>T
ENST00000619732.4:c.568C>T
ENST00000622433.4:c.556C>T
ENST00000628176.2:c.459C>T
NM_001110792.1:c.604C>T
NM_001316337.1:c.289C>T
NM_004992.3:c.568C>T
NM_001316337.2:c.289C>T
NM_001369391.2:c.289C>T
NM_001369392.2:c.289C>T
NM_001369393.2:c.289C>T
NM_001369394.1:c.289C>T
NM_001369394.2:c.289C>T
NM_001386137.1:c.-102C>T
NM_001386138.1:c.-102C>T
NM_001386139.1:c.-102C>T
NM_004992.4:c.568C>T
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Uncertain Significance

Met criteria codes 2
BS2 PS3_Supporting
Not Met criteria codes 6
BS1 PS4 PS2 PP3 PM1 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The NM_004992.4:c.568C>T (p.Arg190Cys) variant in MECP2 is observed in at least 2 unaffected individuals (GeneDx internal database, LabCorp Genetics Inc. internal database) (BS2). Quantitative immunofluorescence localization assays have shown that this variant impacts protein function (PMID: 29431277) (PS3_Supporting). The highest population frequency in gnomAD v4.1 is 0.00002 in the European (Finnish) population (BS1_Not Met). The p.Arg190Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID: 24776741) (PS2 - not met as patient was not described to have features of Rett syndrome). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.626). A missense variant (p.Arg190His) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5- not met). In summary, the p.Arg190Cys variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS3_Supporting) (MECP2 Specifications v3.0; curation approved on 02/28/2025).
Met criteria codes
BS2
The p.Arg190Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (GeneDx internal database, LabCorp Genetics Inc. internal database). (BS2)
PS3_Supporting
Quantitative immunofluorescence localization assays have shown that this variant impacts protein function (PMID: 29431277) (PS3_Supporting).
Not Met criteria codes
BS1
The highest population frequency in gnomAD v4.1 is 0.00002 in the European (Finnish) population. (BS1_Not Met).
PS4
One additional PMID (29655203) is present in HGMD, and reports that this variant was identified in a cohort of individuals who had genetic testing related to epilepsy +/- neurodevelopmental disorders through GeneDx. Individual-level clinical data is not presented in this paper, therefore this evidence would not meet PS4 criteria.
PS2
The p.R190C variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID 24776741) (PS2 - not met due as patient was not described to have features of Rett syndrome).
PP3
Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.626).
PM1
Outside PM1 region
PM5
A missense variant (p.R190H) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5_not met).
Curation History
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