Submissions for variant NM_130839.5(UBE3A):c.2567_2570del (p.Lys856fs)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000147883	SCV001711995	pathogenic	Angelman syndrome	2021-03-26	reviewed by expert panel	curation	The p.Lys836Argfs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated 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). This variant has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 9887341) (PM6). This variant has been observed in at least 4 other individuals with Angelman syndrome (PMID 9887341, 25212744, ClinVar) (PS4). The p.Lys836Argfs variant in UBE3A is absent from gnomAD (PM2_supporting). In summary, the p.Lys836Argfs variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4, PM6, PM2_supporting).
Genetic Services Laboratory, University of Chicago	RCV000147883	SCV000195367	pathogenic	Angelman syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000481125	SCV000568350	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost and replaced with 3 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9887341, 25212744, 19213023, 31031587, 27535533)
Baylor Genetics	RCV000147883	SCV000807249	pathogenic	Angelman syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 2-year-old male with global delays, absent speech, hypertonia, strabismus.
Ambry Genetics	RCV000622970	SCV000848426	pathogenic	Inborn genetic diseases	2022-07-18	criteria provided, single submitter	clinical testing	The c.2507_2510delAAGA (p.K836Rfs*4) alteration, located in exon 10 (coding exon 10) of the UBE3A gene, consists of a deletion of 4 nucleotides from position 2507 to 2510, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration occurs at the 3' terminus of the UBE3A gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration (also designated as 3093del4 and 3093delAAGA) has been reported as a de novo mutation in multiple patients meeting clinical criteria for Angelman syndrome (Fang, 1999; Rapakko, 2004; Hitchins, 2004; Camprubí, 2009; Tzagkaraki, 2013; Sadikovic, 2014; Xiong, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000147883	SCV000890076	pathogenic	Angelman syndrome	2017-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000147883	SCV001215289	pathogenic	Angelman syndrome	2022-09-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 160220). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.3093del4. This premature translational stop signal has been observed in individual(s) with Angelman syndrome (PMID: 9887341, 19213023). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys836Argfs*4) in the UBE3A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the UBE3A protein.
CeGaT Center for Human Genetics Tuebingen	RCV000481125	SCV001248892	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260843	SCV001437939	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000147883	SCV002061721	pathogenic	Angelman syndrome	2021-11-29	criteria provided, single submitter	clinical testing	PVS1, PS2, PS4, PM2
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000147883	SCV003804065	pathogenic	Angelman syndrome	2021-02-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000147883	SCV004809864	uncertain significance	Angelman syndrome	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000147883	SCV000028642	pathogenic	Angelman syndrome	2004-04-30	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000147883	SCV000257507	pathogenic	Angelman syndrome	2007-04-23	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000481125	SCV001739961	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000481125	SCV001953186	likely pathogenic	not provided		no assertion criteria provided	clinical testing