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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Variant: NM_130839.5(UBE3A):c.2563_2568del (p.Leu855_Lys856del)

CA279164

217365 (ClinVar)

Gene: UBE3A
Condition: Angelman syndrome
Inheritance Mode: Autosomal dominant inheritance (with paternal imprinting (HP:0012274))
Link to MONDO
UUID: 46216cc0-af0a-465e-a1b0-ee31dfddaf68

HGVS expressions

NM_130839.5:c.2563_2568del
NM_130839.5(UBE3A):c.2563_2568del (p.Leu855_Lys856del)
NC_000015.10:g.25339191_25339196del
CM000677.2:g.25339191_25339196del
NC_000015.9:g.25584338_25584343del
CM000677.1:g.25584338_25584343del
NC_000015.8:g.23135431_23135436del
NG_009268.1:g.104789_104794del
ENST00000438097.6:c.2503_2508del
ENST00000635914.1:c.*888_*893del
ENST00000636667.1:c.100_105del
ENST00000637886.1:c.2563_2568del
ENST00000638011.1:c.2503_2508del
ENST00000638155.1:c.2503_2508del
ENST00000648336.2:c.2563_2568del
ENST00000649550.1:c.2503_2508del
ENST00000650110.1:c.2572_2577del
ENST00000675177.1:c.2386_2391del
ENST00000232165.7:c.2503_2508del
ENST00000397954.6:c.2572_2577del
ENST00000428984.6:c.2503_2508del
ENST00000438097.5:c.2503_2508del
ENST00000566215.5:c.2503_2508del
ENST00000604860.3:n.514_519del
ENST00000614096.4:c.2563_2568del
ENST00000626176.2:n.374_379del
ENST00000630424.2:c.2503_2508del
NM_000462.3:c.2572_2577del
NM_130838.1:c.2503_2508del
NM_130839.2:c.2563_2568del
NM_000462.5:c.2572_2577del
NM_001354505.1:c.2563_2568del
NM_001354506.1:c.2503_2508del
NM_001354507.1:c.2503_2508del
NM_001354508.1:c.2503_2508del
NM_001354509.1:c.2503_2508del
NM_001354511.1:c.2503_2508del
NM_001354512.1:c.2503_2508del
NM_001354513.1:c.2503_2508del
NM_001354523.1:c.2503_2508del
NM_001354526.1:c.2503_2508del
NM_001354538.1:c.2563_2568del
NM_001354539.1:c.2503_2508del
NM_001354540.1:c.2503_2508del
NM_001354541.1:c.2503_2508del
NM_001354542.1:c.2503_2508del
NM_001354543.1:c.2503_2508del
NM_001354544.1:c.2503_2508del
NM_001354545.1:c.2407_2412del
NM_001354546.1:c.2386_2391del
NM_001354547.1:c.2347_2352del
NM_001354548.1:c.2347_2352del
NM_001354549.1:c.2338_2343del
NM_001354550.1:c.1312_1317del
NM_001354551.1:c.1252_1257del
NM_130838.3:c.2503_2508del
NM_130839.4:c.2563_2568del
NR_146177.1:n.18393-52405_18393-52400del
NR_148916.1:n.3107_3112del
NM_001354506.2:c.2503_2508del
NM_001354507.2:c.2503_2508del
NM_001354508.2:c.2503_2508del
NM_001354509.2:c.2503_2508del
NM_001354511.2:c.2503_2508del
NM_001354512.2:c.2503_2508del
NM_001354513.2:c.2503_2508del
NM_001354523.2:c.2503_2508del
NM_001354538.2:c.2563_2568del
NM_001354539.2:c.2503_2508del
NM_001354540.2:c.2503_2508del
NM_001354541.2:c.2503_2508del
NM_001354542.2:c.2503_2508del
NM_001354543.2:c.2503_2508del
NM_001354544.2:c.2503_2508del
NM_001354545.2:c.2407_2412del
NM_001354546.2:c.2386_2391del
NM_001354547.2:c.2347_2352del
NM_001354548.2:c.2347_2352del
NM_001354549.2:c.2338_2343del
NM_001354550.2:c.1312_1317del
NM_001354551.2:c.1252_1257del
NM_001374461.1:c.2503_2508del
NM_130838.4:c.2503_2508del
NR_148916.2:n.3075_3080del

Pathogenic

Met criteria codes 5
PM2_Supporting PS2_Very Strong PS4 PP4 PM4_Supporting

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.2503_2508del p.(Leu835_Lys836del) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Leu835_Lys836del) variant has been observed in at least 5 individuals with a diagnosis of Angelman syndrome or a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 24796722; ClinVar SCV000829845.4, SCV000491076.2, SCV000332262.4) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (ClinVar SCV000491076.2, SCV000829845.4, SCV000332262.4) (PS2_Very strong). The p.(Leu835_Lys836del) variant causes a change in the length of 2 amino acids in the protein due to an in-frame deletion or insertion in a non-repeat region of UBE3A (PM4_supporting). In summary, the c.2503_2508del p.(Leu835_Lys836del) variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4_strong, PP4, PM2_supporting, PM4_supporting).
Met criteria codes
PM2_Supporting
The p.Leu835_Lys836del variant in UBE3A is absent from gnomAD (PM2_supporting).
PS2_Very Strong
The p.Leu835_Lys836del variant in UBE3A has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with Angleman syndrome (ClinVar SCV000491076.2, SCV000829845.4, SCV000332262.4) (PS2_Very strong).
PS4
The p.Leu835_Lys836del variant has been observed in at least 5 individuals with a diagnosis of Angelman syndrome or a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 24796722; ClinVar SCV000829845.4, SCV000491076.2, SCV000332262.4) (PS4).
PP4
The p.Leu835_Lys836del variant in UBE3A has been reported in individuals with a clinical phenotype suggestive of Angelman syndrome (PMID 24796722, ClinVar SCV000829845.4) (PP4).
PM4_Supporting
The p.Leu835_Lys836del variant causes a change in the length of 2 amino acids in the protein due to an in-frame deletion or insertion in a non-repeat region of UBE3A (PM4_supporting).
Approved on: 2022-06-30
Published on: 2022-06-30
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