rs1064793307

Variant names:

• chr15-25370598-G-A
• rs1064793307
• NM_130839.5:c.1576C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PP4 PP1 PM2_Supporting PS4 PS3_Supporting PM6

This summary comes from the ClinGen Evidence Repository: The c.1576C>T (p.Arg526Cys) variant in the UBE3A gene has been observed in at least 5 individuals with Angelman syndrome (PMID:10647895, 19213023, 23708187, 25212744; GeneDx: internal database) (PS4). The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID:10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID:23708187) (PP1). The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID:10647895) (PP4). The p.Arg526Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting). Protein expression analysis in transfected cell lines has shown that this variant destabilizes the protein, demonstrated by significantly reduced protein levels (PMID:26255772) (PS3_Supporting). In summary, the p.Arg526Cys variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4, PM6, PP1, PP3, PP4, PM2_supporting, PS3_supporting) (UBE3A specifications version 5.0; curation approved on 2/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16619907/MONDO:0007113/037

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.30

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.1576C>T	p.Arg526Cys	missense_variant	Exon 6 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1576C>T	p.Arg526Cys	missense_variant	Exon 6 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:3

Feb 28, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1576C>T (p.Arg526Cys) variant in the UBE3A gene has been observed in at least 5 individuals with Angelman syndrome (PMID: 10647895, 19213023, 23708187, 25212744; GeneDx: internal database) (PS4). The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID: 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID: 23708187) (PP1). The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID: 10647895) (PP4). The p.Arg526Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting). Protein expression analysis in transfected cell lines has shown that this variant destabilizes the protein, demonstrated by significantly reduced protein levels (PMID: 26255772) (PS3_Supporting). In summary, the p.Arg526Cys variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4, PM6, PP1, PP3, PP4, PM2_supporting, PS3_supporting) (UBE3A specifications version 5.0; curation approved on 2/28/2025). -

Jan 21, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 506 of the UBE3A protein (p.Arg506Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Angelman syndrome (PMID: 19213023, 26255772). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 418572). 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) performed at Invitae indicates that this missense variant is expected to disrupt UBE3A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects UBE3A function (PMID: 33607653). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

UBE3A-related disorder Pathogenic:1

Jan 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	.;.;.;.;.;.;.;.;.;D;.;.;.;D;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;.;.;.;.;H;.;.;.;H;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.0	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.
Polyphen		1.0	.;D;.;.;.;D;.;D;.;D;.;.;.;D;.
Vest4		0.98, 0.89, 0.96, 0.88, 0.96, 0.96
MutPred		0.92		.;.;.;.;.;.;.;.;.;Loss of catalytic residue at R529 (P = 0.0445);.;.;.;Loss of catalytic residue at R529 (P = 0.0445);.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064793307; hg19: chr15-25615745; COSMIC: COSV51660557; COSMIC: COSV51660557;