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_130839.5(UBE3A):c.2419A>G (p.Thr807Ala)

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Curation History
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CA7435364

418562 (ClinVar)

Gene: UBE3A

Condition: Angelman syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1acbee77-20a7-4697-bc4a-de8bb1c9c117

Approved on: 2023-06-20

Published on: 2023-06-21

HGVS expressions

NM_130839.5:c.2419A>G

NM_130839.5(UBE3A):c.2419A>G (p.Thr807Ala)

NC_000015.10:g.25340164T>C

CM000677.2:g.25340164T>C

NC_000015.9:g.25585311T>C

CM000677.1:g.25585311T>C

NC_000015.8:g.23136404T>C

NG_009268.1:g.103818A>G

ENST00000438097.6:c.2359A>G

ENST00000635914.1:c.2359A>G

ENST00000636667.1:c.-45A>G

ENST00000637886.1:c.2419A>G

ENST00000638011.1:c.2359A>G

ENST00000638155.1:c.2359A>G

ENST00000648336.2:c.2419A>G

ENST00000649550.1:c.2359A>G

ENST00000650110.1:c.2428A>G

ENST00000675177.1:c.2242A>G

ENST00000675593.1:n.5115A>G

ENST00000232165.7:c.2359A>G

ENST00000397954.6:c.2428A>G

ENST00000428984.6:c.2359A>G

ENST00000438097.5:c.2359A>G

ENST00000566215.5:c.2359A>G

ENST00000604860.3:n.370A>G

ENST00000614096.4:c.2419A>G

ENST00000626176.2:n.230A>G

ENST00000630424.2:c.2359A>G

NM_000462.3:c.2428A>G

NM_130838.1:c.2359A>G

NM_130839.2:c.2419A>G

NM_000462.5:c.2428A>G

NM_001354505.1:c.2419A>G

NM_001354506.1:c.2359A>G

NM_001354507.1:c.2359A>G

NM_001354508.1:c.2359A>G

NM_001354509.1:c.2359A>G

NM_001354511.1:c.2359A>G

NM_001354512.1:c.2359A>G

NM_001354513.1:c.2359A>G

NM_001354523.1:c.2359A>G

NM_001354526.1:c.2359A>G

NM_001354538.1:c.2419A>G

NM_001354539.1:c.2359A>G

NM_001354540.1:c.2359A>G

NM_001354541.1:c.2359A>G

NM_001354542.1:c.2359A>G

NM_001354543.1:c.2359A>G

NM_001354544.1:c.2359A>G

NM_001354545.1:c.2263A>G

NM_001354546.1:c.2242A>G

NM_001354547.1:c.2203A>G

NM_001354548.1:c.2203A>G

NM_001354549.1:c.2194A>G

NM_001354550.1:c.1168A>G

NM_001354551.1:c.1108A>G

NM_130838.3:c.2359A>G

NM_130839.4:c.2419A>G

NR_146177.1:n.18393-51432T>C

NR_148916.1:n.2963A>G

NM_001354506.2:c.2359A>G

NM_001354507.2:c.2359A>G

NM_001354508.2:c.2359A>G

NM_001354509.2:c.2359A>G

NM_001354511.2:c.2359A>G

NM_001354512.2:c.2359A>G

NM_001354513.2:c.2359A>G

NM_001354523.2:c.2359A>G

NM_001354538.2:c.2419A>G

NM_001354539.2:c.2359A>G

NM_001354540.2:c.2359A>G

NM_001354541.2:c.2359A>G

NM_001354542.2:c.2359A>G

NM_001354543.2:c.2359A>G

NM_001354544.2:c.2359A>G

NM_001354545.2:c.2263A>G

NM_001354546.2:c.2242A>G

NM_001354547.2:c.2203A>G

NM_001354548.2:c.2203A>G

NM_001354549.2:c.2194A>G

NM_001354550.2:c.1168A>G

NM_001354551.2:c.1108A>G

NM_001374461.1:c.2359A>G

NM_130838.4:c.2359A>G

NR_148916.2:n.2931A>G

Uncertain Significance

PM2_Supporting PP3 PS4_Supporting

PS3

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.2359A>G p.Thr787Ala variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_Supporting). The p.Thr787Ala variant has been observed in multiple individuals with seizures, where at least 2 of these cases are known to be maternally inherited (Invitae internal data) (PS4_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Functional studies suggest p.Thr787Ala is a gain of function variant that increases UBE3A ubiquitin ligase activity (PMID: 34815418). However, as loss of function is the known mechanism of UBE3A-associated disease, this evidence has not been applied. In summary, the p.Thr787Ala variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_Supporting, PS4_Supporting, PP3).

PM2_Supporting

The c.2359A>G p.Thr787Ala variant in UBE3A (NM_130838.2) is absent from gnomAD.

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.

PS4_Supporting

The p.Thr787Ala variant has been observed in multiple individuals with seizures, where at least 2 of these cases are known to be maternally inherited (ClinVar SCV002164454.2) (PS4_Supporting).

PS3

Functional studies suggest p.Thr787Ala is a gain of function variant that increases UBE3A ubiquitin ligase activity (PMID: 34815418). However, as loss of function is a known mechanism of UBE3A-associated disease, this evidence has not been applied.

Curation History

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