Submissions for variant NM_206933.4(USH2A):c.9571-2A>G

gnomAD frequency: 0.00003  dbSNP: rs751111524

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670550	SCV000795413	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-11-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057476	SCV001221972	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 48 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs751111524, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 28041643, 28559085, 28981474). ClinVar contains an entry for this variant (Variation ID: 438033). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075684	SCV001241312	pathogenic	Retinal dystrophy	2019-04-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002231177	SCV002512003	pathogenic	Usher syndrome	2022-04-27	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9571-2A>G alters a conserved nucleotide 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: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250638 control chromosomes. c.9571-2A>G has been reported in the literature as compound heterozygous genotypes in multiple individuals affected with features of Usher Syndrome such as Inherited Retinal Disease (example, Stone_2017, Carss_2017, Comander_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001057476	SCV003814236	likely pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003446101	SCV004172035	likely pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001829438	SCV004172036	likely pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003446101	SCV004208342	pathogenic	Retinitis pigmentosa 39	2024-03-20	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505005	SCV000598842	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001829438	SCV002088395	pathogenic	Usher syndrome type 2A	2020-08-27	no assertion criteria provided	clinical testing