Submissions for variant NM_130839.5(UBE3A):c.1576C>T (p.Arg526Cys)

dbSNP: rs1064793307

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	RCV000690582	SCV001712009	likely pathogenic	Angelman syndrome	2021-03-25	reviewed by expert panel	curation	The c.1516C>T (p.Arg506Cys) variant in UBE3A is absent from gnomAD (PM2_supporting). This variant has been observed in at least 3 individuals with Angelman syndrome (PMID 10647895, 19213023, 23708187) (PS4_moderate). The p.Arg506Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in an individual with Angelman syndrome (PMID 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID 23708187) (PP1). Protein expression analysis in transfected cell lines has shown that this variant impacts protein function (PMID: 26255772) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg506Cys variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4_moderate, PM6, PS3_supporting, PM2_supporting, PP1, PP3, PP4).
GeneDx	RCV000478539	SCV000565710	pathogenic	not provided	2017-03-17	criteria provided, single submitter	clinical testing	The R506C variant in the UBE3A gene has been reported previously in association with Angelman syndrome (Baumer et al., 1999; Camprubi et al., 2009; Carvill et al., 2013; Yi et al., 2015). The R506C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R506C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R506C as a pathogenic variant.
Invitae	RCV000690582	SCV000818272	likely pathogenic	Angelman syndrome	2018-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 506 of the UBE3A protein (p.Arg506Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Angelman syndrome (PMID: 26255772). This variant has also been reported to be maternally inherited in an unrelated individual affected with Angelman syndrome (PMID: 19213023). ClinVar contains an entry for this variant (Variation ID: 418572). Experimental studies have shown that this missense change results in reduced UBE3A protein expression (PMID: 26255772). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000478539	SCV001248896	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000690582	SCV002556917	pathogenic	Angelman syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 506 of the UBE3A protein (p.Arg506Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Angelman syndrome (PMID: 26255772). This variant has also been reported to be maternally inherited in an unrelated individual affected with Angelman syndrome (PMID: 19213023). ClinVar contains an entry for this variant (Variation ID: 418572). Experimental studies have shown that this missense change results in reduced UBE3A protein expression (PMID: 26255772). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003900014	SCV004715068	pathogenic	UBE3A-related condition	2024-01-10	criteria provided, single submitter	clinical testing	The UBE3A c.1516C>T variant is predicted to result in the amino acid substitution p.Arg506Cys. This variant has been reported as maternally-inherited or de novo in individuals with Angelman syndrome (Baumer et al. 1999. PubMed ID: 10647895; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S1, Du et al. 2022. PubMed ID: 36011358). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic.