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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_130838.3(UBE3A):c.1516C>T (p.Arg506Cys)

CA16619907

418572 (ClinVar)

Gene: UBE3A
Condition: Angelman syndrome
Inheritance Mode: Autosomal dominant inheritance (with paternal imprinting (HP:0012274))
Link to MONDO
UUID: ee548715-7a99-499a-aff8-b87446f02a4c
Approved on: 2021-03-25
Published on: 2021-05-10

HGVS expressions

NM_130838.3:c.1516C>T
NM_130838.3(UBE3A):c.1516C>T (p.Arg506Cys)
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_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
NM_130839.5:c.1576C>T
NR_148916.2:n.2092C>T

Likely Pathogenic

Met criteria codes 7
PS3_Supporting PS4_Moderate PM2_Supporting PP1 PP4 PP3 PM6

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The c.1516C>T (p.Arg506Cys) variant in UBE3A is absent from gnomAD (PM2_supporting). This variant has been observed in at least 3 individuals with Angelman syndrome (PMID 10647895, 19213023, 23708187) (PS4_moderate). The p.Arg506Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in an individual with Angelman syndrome (PMID 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID 23708187) (PP1). Protein expression analysis in transfected cell lines has shown that this variant impacts protein function (PMID: 26255772) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg506Cys variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4_moderate, PM6, PS3_supporting, PM2_supporting, PP1, PP3, PP4).
Met criteria codes
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)
Protein expression analysis in transfected cell lines has shown that this variant destabilises the protein, demonstrated by significantly reduced protein levels via western blotting- see figure 2 PubMed:26255772
PS4_Moderate
The c.1516C>T (p.Arg506Cys) variant in the UBE3A gene has been observed in at least 3 other individuals with Angelman syndrome (PMID 10647895, 19213023, 23708187)
Study of 500 patients with a range of epileptic encephalopathy phenotypes, tested by targeted massively parallel resequencing of known epileptic encephalopathy genes. Variant was identified in 1 patient with epileptic encephalopathy and features suggestive of Angelman syndrome. The variant was found to be inherited from the unaffected mother, and was also present in an affected sibling PubMed:23708187
Study of a large cohort of Spanish Angelman syndrome patients screened to variants in UBE3A. Variant was identified in 1 AS patient and was found to be maternally inherited PubMed:19213023
Study of 101 Angelman syndrome patients screened for variants in UBE3A. Variant was identified in 1 AS case and found to be de novo (listed as 2102 C to T Arg506Cys - refers to accession number U84404). PubMed:10647895
PM2_Supporting
The c.1516C>T (p.Arg506Cys) variant in the UBE3A gene is absent from gnomAD
PP1
The variant has been reported to segregate in two affected family members with Angelman syndrome
Study of 500 patients with a range of epileptic encephalopathy phenotypes, tested by targeted massively parallel resequencing of known epileptic encephalopathy genes. Variant was identified in 1 patient with epileptic encephalopathy and features suggestive of Angelman syndrome. The variant was found to be inherited from the unaffected mother, and was also present in an affected sibling. PubMed:23708187
PP4
A patient in the literature is reported to have a clinical phenotype suggestive of Angelman syndrome.
PP3
REVEL score 0.866. Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PM6
The c.1516C>T (p.Arg506Cys) variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID 10647895).
Study of 101 Angelman syndrome patients screened for variants in UBE3A. Variant was identified in 1 AS case and found to be de novo (listed as 2102 C to T Arg506Cys - refers to accession number U84404). PubMed:10647895
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