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 obtained from curated document aligns with the Allele Registry but not with ClinVar data

Variant: NM_130839.5(UBE3A):c.1576C>T (p.Arg526Cys)

CA16619907

418572 (ClinVar)

Gene: UBE3A
Condition: Angelman syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ee548715-7a99-499a-aff8-b87446f02a4c
Approved on: 2025-02-28
Published on: 2025-03-07

HGVS expressions

NM_130839.5:c.1576C>T
NM_130839.5(UBE3A):c.1576C>T (p.Arg526Cys)
NC_000015.10:g.25370598G>A
CM000677.2:g.25370598G>A
NC_000015.9:g.25615745G>A
CM000677.1:g.25615745G>A
NC_000015.8:g.23166838G>A
NG_009268.1:g.73384C>T
ENST00000438097.6:c.1516C>T
ENST00000625778.3:c.1516C>T
ENST00000635914.1:c.1516C>T
ENST00000637886.1:c.1576C>T
ENST00000638011.1:c.1516C>T
ENST00000638155.1:c.1516C>T
ENST00000648336.2:c.1576C>T
ENST00000649550.1:c.1516C>T
ENST00000650110.1:c.1585C>T
ENST00000675000.1:n.2251C>T
ENST00000675177.1:c.1399C>T
ENST00000675593.1:n.4272C>T
ENST00000232165.7:c.1516C>T
ENST00000397954.6:c.1585C>T
ENST00000428984.6:c.1516C>T
ENST00000438097.5:c.1516C>T
ENST00000566215.5:c.1516C>T
ENST00000614096.4:c.1576C>T
ENST00000625778.2:c.1516C>T
ENST00000630424.2:c.1516C>T
NM_000462.3:c.1585C>T
NM_130838.1:c.1516C>T
NM_130839.2:c.1576C>T
NM_000462.5:c.1585C>T
NM_001354505.1:c.1576C>T
NM_001354506.1:c.1516C>T
NM_001354507.1:c.1516C>T
NM_001354508.1:c.1516C>T
NM_001354509.1:c.1516C>T
NM_001354511.1:c.1516C>T
NM_001354512.1:c.1516C>T
NM_001354513.1:c.1516C>T
NM_001354523.1:c.1516C>T
NM_001354526.1:c.1516C>T
NM_001354538.1:c.1576C>T
NM_001354539.1:c.1516C>T
NM_001354540.1:c.1516C>T
NM_001354541.1:c.1516C>T
NM_001354542.1:c.1516C>T
NM_001354543.1:c.1516C>T
NM_001354544.1:c.1516C>T
NM_001354545.1:c.1576C>T
NM_001354546.1:c.1399C>T
NM_001354547.1:c.1516C>T
NM_001354548.1:c.1516C>T
NM_001354549.1:c.1516C>T
NM_001354550.1:c.361+4867C>T
NM_001354551.1:c.301+4867C>T
NM_130838.3:c.1516C>T
NM_130839.4:c.1576C>T
NR_146177.1:n.18393-20998G>A
NR_148916.1:n.2124C>T
NM_001354506.2:c.1516C>T
NM_001354507.2:c.1516C>T
NM_001354508.2:c.1516C>T
NM_001354509.2:c.1516C>T
NM_001354511.2:c.1516C>T
NM_001354512.2:c.1516C>T
NM_001354513.2:c.1516C>T
NM_001354523.2:c.1516C>T
NM_001354538.2:c.1576C>T
NM_001354539.2:c.1516C>T
NM_001354540.2:c.1516C>T
NM_001354541.2:c.1516C>T
NM_001354542.2:c.1516C>T
NM_001354543.2:c.1516C>T
NM_001354544.2:c.1516C>T
NM_001354545.2:c.1576C>T
NM_001354546.2:c.1399C>T
NM_001354547.2:c.1516C>T
NM_001354548.2:c.1516C>T
NM_001354549.2:c.1516C>T
NM_001354550.2:c.361+4867C>T
NM_001354551.2:c.301+4867C>T
NM_001374461.1:c.1516C>T
NM_130838.4:c.1516C>T
NR_148916.2:n.2092C>T
More

Pathogenic

Met criteria codes 7
PM6 PM2_Supporting PS4 PP1 PP4 PP3 PS3_Supporting

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 UBE3A Version 5.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The c.1576C>T (p.Arg526Cys) variant in the UBE3A gene has been observed in at least 5 individuals with Angelman syndrome (PMID: 10647895, 19213023, 23708187, 25212744; GeneDx: internal database) (PS4). The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID: 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID: 23708187) (PP1). The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID: 10647895) (PP4). The p.Arg526Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting). Protein expression analysis in transfected cell lines has shown that this variant destabilizes the protein, demonstrated by significantly reduced protein levels (PMID: 26255772) (PS3_Supporting). In summary, the p.Arg526Cys variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4, PM6, PP1, PP3, PP4, PM2_supporting, PS3_supporting) (UBE3A specifications version 5.0; curation approved on 2/28/2025).
Met criteria codes
PM6
The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID: 10647895).
PM2_Supporting
The p.Arg506Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting).
PS4
The p.Arg526Cys variant in the UBE3A gene has been observed in at least 5 other individuals with Angelman syndrome (PMID: 10647895, 19213023, 23708187, 25212744; GeneDx: internal database). (PS4)
PP1
The variant has been reported to segregate in two informative meioses (PMID 23708187) (PP1).
PP4
The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 10647895) (PP4).
PP3
The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3).
PS3_Supporting
Protein expression analysis in transfected cell lines has shown that this variant destabilises the protein, demonstrated by significantly reduced protein levels (PMID: 26255772)
Curation History
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