Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_130839.5(UBE3A):c.1472_1476delATTAT(p.Tyr491fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
UBE3A (HGNC:12496): (ubiquitin protein ligase E3A) This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]
SNHG14 (HGNC:37462): (small nucleolar RNA host gene 14) This gene is located within the Prader-Willi critical region and produces a long, spliced paternally-imprinted RNA that initiates within a common upstream promoter region shared by the SNRPN (small nuclear ribonucleoprotein polypeptide N) and SNURF genes. This transcript serves as a host RNA for the small nucleolar RNA, C/D box 115 and 116 clusters. This RNA extends in antisense into the region of the ubiquitin protein ligase E3A gene (UBE3A), and is thought to regulate imprinted expression of UBE3A in the brain. This transcript undergoes extensive alternative splicing, and may initiate and terminate at multiple locations within this genomic region. The full-length structure of all splice forms is not determined. [provided by RefSeq, Mar 2017]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-25370697-CATAAT-C is Pathogenic according to our data. Variant chr15-25370697-CATAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 217362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-25370697-CATAAT-C is described in Lovd as [Pathogenic].
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jan 01, 2019
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Jul 18, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). This variant has been reported in 2 siblings and an unrelated individual affected with Angelman syndrome (PMID: 14981718, 19213023). This variant has also been reported as c.1993del5 and c.1407_1411del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 217362). This sequence change creates a premature translational stop signal (p.Tyr471*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. -
not provided Pathogenic:2
Mar 10, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25212744, 27174604, 36011358, 31440721, 14981718) -
Mar 06, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Epileptic encephalopathy Pathogenic:1
Jan 02, 2020
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter