Submissions for variant NM_130839.5(UBE3A):c.2563C>T (p.Leu855Phe)

dbSNP: rs587783097

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000147882	SCV001711997	likely pathogenic	Angelman syndrome	2021-03-26	reviewed by expert panel	curation	The p.Leu835Phe variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Leu835Phe variant has been observed in at least 1 other affected individual (PMID 29655203) (PS4_Supporting). The variant has been reported to segregate in three informative meioses (PP1_moderate). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu835Phe variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PP4). In summary, the p.Leu835Phe variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PS4_supporting, PP1_moderate, PP3, PP4).
GeneDx	RCV000144763	SCV000190979	uncertain significance	not provided	2013-02-28	criteria provided, single submitter	clinical testing	.Leu855Phe (CTT>TTT): c.2563 C>T in exon 13 of the UBE3A gene (NM_130839.1) The novel Leu855Phe missense change has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. An external variant database has not identifiedLeu855Phe in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Leucine and Phenylalanine are both uncharged, non-polar amino acids. However, it alters a highly conserved position in the HECT domain of the protein where multiple other missense variants have been reported in association with Angelman syndrome, and multiple in silico algorithms predict it may be damaging to protein structure/function. Therefore, based on the currently available information, Leu855Phe is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded.
Genetic Services Laboratory, University of Chicago	RCV000147882	SCV000195366	likely pathogenic	Angelman syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002274930	SCV002562244	uncertain significance	See cases	2022-06-24	criteria provided, single submitter	clinical testing	ACMG categories: PM2