Submissions for variant NM_130839.5(UBE3A):c.2096A>C (p.Lys699Thr)

gnomAD frequency: 0.00007  dbSNP: rs202161423

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000144356	SCV004176025	benign	Angelman syndrome	2023-12-06	reviewed by expert panel	curation	The allele frequency of The p.Lys679Thr variant in UBE3A (NM_130838.2) is 0.03187% in European (non-Finnish) sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Lys679Thr variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). In summary, the p.Lys679Thr variant in UBE3A (NM_130838.2) is classified as benign based on the ACMG/AMP criteria (BA1, BP5).
GeneDx	RCV000766996	SCV000191057	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25212744)
Genetic Services Laboratory, University of Chicago	RCV000192972	SCV000249351	uncertain significance	not specified	2015-02-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144356	SCV000952986	uncertain significance	Angelman syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 679 of the UBE3A protein (p.Lys679Thr). This variant is present in population databases (rs202161423, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 156144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UBE3A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000766996	SCV004131435	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000144356	SCV000188533	uncertain significance	Angelman syndrome	2014-02-14	no assertion criteria provided	clinical testing	possible diagnosis of Angelman syndrome
PreventionGenetics, part of Exact Sciences	RCV003927415	SCV004740789	likely benign	UBE3A-related disorder	2022-11-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).