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]

Variant: NM_130839.5(UBE3A):c.1421_1422del (p.Phe474fs)

CA333316

155951 (ClinVar)

Gene: UBE3A
Condition: Angelman syndrome
Inheritance Mode: Autosomal dominant inheritance (with paternal imprinting (HP:0012274))
Link to MONDO
UUID: 362d1361-0a41-4485-abe1-5848323f8ea2
Approved on: 2023-12-06
Published on: 2023-12-11

HGVS expressions

NM_130839.5:c.1421_1422del
NM_130839.5(UBE3A):c.1421_1422del (p.Phe474fs)
NC_000015.10:g.25370754_25370755del
CM000677.2:g.25370754_25370755del
NC_000015.9:g.25615901_25615902del
CM000677.1:g.25615901_25615902del
NC_000015.8:g.23166994_23166995del
NG_009268.1:g.73229_73230del
ENST00000438097.6:c.1361_1362del
ENST00000625778.3:c.1361_1362del
ENST00000635914.1:c.1361_1362del
ENST00000637886.1:c.1421_1422del
ENST00000638011.1:c.1361_1362del
ENST00000638155.1:c.1361_1362del
ENST00000648336.2:c.1421_1422del
ENST00000649550.1:c.1361_1362del
ENST00000650110.1:c.1430_1431del
ENST00000675000.1:n.2096_2097del
ENST00000675177.1:c.1244_1245del
ENST00000675593.1:n.4117_4118del
ENST00000232165.7:c.1361_1362del
ENST00000397954.6:c.1430_1431del
ENST00000428984.6:c.1361_1362del
ENST00000438097.5:c.1361_1362del
ENST00000566215.5:c.1361_1362del
ENST00000614096.4:c.1421_1422del
ENST00000625778.2:c.1361_1362del
ENST00000630424.2:c.1361_1362del
NM_000462.3:c.1430_1431del
NM_130838.1:c.1361_1362del
NM_130839.2:c.1421_1422del
NM_000462.5:c.1430_1431del
NM_001354505.1:c.1421_1422del
NM_001354506.1:c.1361_1362del
NM_001354507.1:c.1361_1362del
NM_001354508.1:c.1361_1362del
NM_001354509.1:c.1361_1362del
NM_001354511.1:c.1361_1362del
NM_001354512.1:c.1361_1362del
NM_001354513.1:c.1361_1362del
NM_001354523.1:c.1361_1362del
NM_001354526.1:c.1361_1362del
NM_001354538.1:c.1421_1422del
NM_001354539.1:c.1361_1362del
NM_001354540.1:c.1361_1362del
NM_001354541.1:c.1361_1362del
NM_001354542.1:c.1361_1362del
NM_001354543.1:c.1361_1362del
NM_001354544.1:c.1361_1362del
NM_001354545.1:c.1421_1422del
NM_001354546.1:c.1244_1245del
NM_001354547.1:c.1361_1362del
NM_001354548.1:c.1361_1362del
NM_001354549.1:c.1361_1362del
NM_001354550.1:c.361+4712_361+4713del
NM_001354551.1:c.301+4712_301+4713del
NM_130838.3:c.1361_1362del
NM_130839.4:c.1421_1422del
NR_146177.1:n.18393-20842_18393-20841del
NR_148916.1:n.1969_1970del
NM_001354506.2:c.1361_1362del
NM_001354507.2:c.1361_1362del
NM_001354508.2:c.1361_1362del
NM_001354509.2:c.1361_1362del
NM_001354511.2:c.1361_1362del
NM_001354512.2:c.1361_1362del
NM_001354513.2:c.1361_1362del
NM_001354523.2:c.1361_1362del
NM_001354538.2:c.1421_1422del
NM_001354539.2:c.1361_1362del
NM_001354540.2:c.1361_1362del
NM_001354541.2:c.1361_1362del
NM_001354542.2:c.1361_1362del
NM_001354543.2:c.1361_1362del
NM_001354544.2:c.1361_1362del
NM_001354545.2:c.1421_1422del
NM_001354546.2:c.1244_1245del
NM_001354547.2:c.1361_1362del
NM_001354548.2:c.1361_1362del
NM_001354549.2:c.1361_1362del
NM_001354550.2:c.361+4712_361+4713del
NM_001354551.2:c.301+4712_301+4713del
NM_001374461.1:c.1361_1362del
NM_130838.4:c.1361_1362del
NR_148916.2:n.1937_1938del
More

Pathogenic

Met criteria codes 3
PVS1 PS4_Moderate PM2_Supporting
Not Met criteria codes 12
PP4 PM3 PM1 PM6 BS2 BS3 BS1 BP5 BP2 BA1 PS2 PS3

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 4.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Phe474fs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Phe474fs variant has been observed in 3 individuals with Angleman syndrome (PMID 25212744, internal database - Invitae) (PS4_moderate). This variant is absent from gnomAD v4 (PM2_supporting). In summary, the p.Phe474fs variant in UBE3A is classified as Pathogenic based on the ACMG/AMP criteria (PVS1, PS4_moderate, PM2_supporting).
Met criteria codes
PVS1
The p.Phe474fs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic
PS4_Moderate
The p.Phe474fs variant has been observed in 3 individuals with Angleman syndrome (PMID 25212744, internal database - Invitae)
PM2_Supporting
The p.Phe474fs variant in UBE3A is absent from gnomAD v4
Not Met criteria codes
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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