rs1064793307
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS3_SupportingPM6PP3PP4PP1PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16619907/MONDO:0007113/016
Frequency
Consequence
NM_130839.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBE3A | NM_130839.5 | c.1576C>T | p.Arg526Cys | missense_variant | 6/13 | ENST00000648336.2 | |
SNHG14 | NR_146177.1 | n.18393-20998G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBE3A | ENST00000648336.2 | c.1576C>T | p.Arg526Cys | missense_variant | 6/13 | NM_130839.5 | P1 | ||
SNHG14 | ENST00000656420.1 | n.5457-48190G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Angelman syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 21, 2021 | 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. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Mar 25, 2021 | 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2018 | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
UBE3A-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 10, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at