Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA199325

143749 (ClinVar)

Gene: MECP2

Condition: Rett syndrome

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 431d1239-3305-42a4-967d-adae00522f20

Approved on: 2022-07-28

Published on: 2022-09-06

HGVS expressions

NM_001110792.2:c.961C>T

NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)

NC_000023.11:g.154030903G>A

CM000685.2:g.154030903G>A

NC_000023.10:g.153296354G>A

CM000685.1:g.153296354G>A

NC_000023.9:g.152949548G>A

NG_007107.2:g.111225C>T

NG_007107.3:g.111201C>T

ENST00000303391.11:c.925C>T

ENST00000453960.7:c.961C>T

ENST00000637917.1:n.99C>T

ENST00000303391.10:c.925C>T

ENST00000407218.5:c.*297C>T

ENST00000453960.6:c.961C>T

ENST00000619732.4:c.925C>T

ENST00000622433.4:c.911C>T

ENST00000628176.2:c.*297C>T

NM_001110792.1:c.961C>T

NM_001316337.1:c.646C>T

NM_004992.3:c.925C>T

NM_001316337.2:c.646C>T

NM_001369391.2:c.646C>T

NM_001369392.2:c.646C>T

NM_001369393.2:c.646C>T

NM_001369394.1:c.646C>T

NM_001369394.2:c.646C>T

NM_001386137.1:c.256C>T

NM_001386138.1:c.256C>T

NM_001386139.1:c.256C>T

NM_004992.4:c.925C>T

Pathogenic

PS2_Very Strong PM2_Supporting PS4 PP4

BP4 PP3 PM1

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4).

PS2_Very Strong

The p.Arg309Trp variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with clinical features consistent with MECP2-related disease (PMID: 31178897, 26936630) (PS2_very strong).

PM2_Supporting

The p.Arg309Trp variant in MECP2 is absent from gnomAD (PM2_supporting).

PS4

The p.Arg309Trp variant has been observed in at least 5 individuals with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID: 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4).

PP4

The p.Arg309Trp variant in MECP2 has been reported in individuals with a clinical phenotype suggestive of Rett syndrome (PMID: 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PP4).

BP4

Computational prediction analysis tools are inconclusive for this variant (REVEL 0.729).

PP3

Computational prediction analysis tools are inconclusive for this variant (REVEL 0.729).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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