Submissions for variant NM_130839.5(UBE3A):c.2563_2568del (p.Leu855_Lys856del)

dbSNP: rs863225070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000701063	SCV002540707	pathogenic	Angelman syndrome	2022-06-30	reviewed by expert panel	curation	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).
Eurofins Ntd Llc (ga)	RCV000201266	SCV000332262	likely pathogenic	not provided	2017-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000201266	SCV000491076	pathogenic	not provided	2019-08-24	criteria provided, single submitter	clinical testing	Reported using alternate nomenclature c.3090_3095delCTTAAA in two unrelated patients with Angelman syndrome in published literature (Goto et al., 2015); In-frame deletion of two amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24796722)
Invitae	RCV000701063	SCV000829845	pathogenic	Angelman syndrome	2021-02-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Angelman syndrome (PMID: 24796722). In at least one individual the variant was observed to be de novo. This variant is also known as 3090_3095delCTTAAA (p.853_854delLK). ClinVar contains an entry for this variant (Variation ID: 217365). This variant is not present in population databases (ExAC no frequency). This variant, c.2503_2508del, results in the deletion of 2 amino acid(s) of the UBE3A protein (p.Leu835_Lys836del), but otherwise preserves the integrity of the reading frame.
3billion	RCV000701063	SCV003842011	pathogenic	Angelman syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000217365 / PMID: 24796722). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201266	SCV000256054	likely pathogenic	not provided	2015-03-06	no assertion criteria provided	clinical testing