Variant: NM_001110792.2(MECP2):c.784C>T (p.Arg262Cys)

Version: 3.0
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CA205183

211466 (ClinVar)

Gene: MECP2 (HGNC:4204)

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

UUID: 42d1d263-dfac-4cab-832f-a8ddefada4fb

Approved on: 2025-10-28

Published on: 2025-12-23

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

Benign

• Met criteria codes: BP5 BS2 PP3 PM6 BA1

• Not Met criteria codes: BP4 PS4 PM5 PM1

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 5.0.0

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The highest population minor allele frequency of the p.Arg250Cys variant in MECP2 (NM_004992.4) in gnomAD v4.1.0 is 0.0006301 in the "remaining" population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.000083) for BA1, and therefore meets this criterion (BA1). The p.Arg250Cys variant is observed in at least 9 unaffected individuals (PMID: 25649377; internal database - GeneDx; internal database - LabCorp (formerly Invitae)) (BS2). The p.Arg250Cys variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Ambry; internal database - LabCorp (formerly Invitae)) (BP5). The p.Arg250Cys variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with developmental and epileptic encephalopathy (PMID: 38074073) (PM6). The p.Arg250Cys variant has been observed in at least 4 individuals with a neurodevelopmental phenotype (PMID: 30405208, 38074073, 26350204, 25649377); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Because this variant has been observed in at least 9 unaffected individuals and 2 individuals with an alternate molecular diagnosis, and has been reported in gnomAD v4.1.0 at a frequency that meets the ClinGen Rett and Angelman-like Disorders VCEP threshold for BA1, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to override the PM6 and PP3 criteria and classified this variant as Benign (BA1, BS2, BP5). (MECP2 Specifications v5.0; curation approved on 10/28/2025)

Met criteria codes

• BP5: The p.Arg250Cys variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Ambry; internal database - LabCorp (formerly Invitae)) (BP5).
• BS2: The p.Arg250Cys variant is observed in at least 9 unaffected individuals (PMID: 25649377; internal database - GeneDx; internal database - LabCorp (formerly Invitae)).
• PP3: Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
• PM6: The p.Arg250Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with developmental and epileptic encephalopathy (PMID: 38074073) (PM6).
• BA1: The highest population minor allele frequency of the p.Arg250Cys variant in MECP2 (NM_004992.4) in gnomAD v4.1.0 is 0.0006301 in the "remaining" population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.000083) for BA1, and therefore meets this criterion (BA1).

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The p.Arg250Cys variant has been observed in at least 4 individuals with a neurodevelopmental phenotype (PMID: 30405208, 38074073, 26350204, 25649377); however PS4 cannot be applied at any strength due to the gnomAD frequency.
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline