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

CA199325

143749 (ClinVar)

Gene: MECP2
Condition: Rett syndrome
Inheritance Mode: X-linked inheritance
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
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Pathogenic

Met criteria codes 4
PM2_Supporting PS4 PP4 PS2_Very Strong
Not Met criteria codes 3
PP3 PM1 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.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).
Met criteria codes
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).
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).
Not Met criteria codes
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
BP4
Computational prediction analysis tools are inconclusive for this variant (REVEL 0.729).
Curation History
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