Submissions for variant NM_206933.4(USH2A):c.4251+1del

dbSNP: rs2102460236

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381744	SCV001580242	pathogenic	not provided	2020-05-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with USH2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1417Hisfs*15) in the USH2A gene. It is expected to result in an absent or disrupted protein product.
DBGen Ocular Genomics	RCV001587388	SCV001816014	pathogenic	Retinitis pigmentosa 39	2021-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003120593	SCV003801317	likely pathogenic	Usher syndrome	2023-01-21	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4251+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250690 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4251+1delG in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001587388	SCV004172151	likely pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003446736	SCV004172152	likely pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing