Submissions for variant NM_206933.4(USH2A):c.14792-2A>G

gnomAD frequency: 0.00002  dbSNP: rs137853923

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087007	SCV001205715	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 100610). Disruption of this splice site has been observed in individuals with Usher syndrome (Invitae). This variant is present in population databases (rs137853923, gnomAD 0.002%). This sequence change affects an acceptor splice site in intron 67 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).
Blueprint Genetics	RCV001074825	SCV001240425	pathogenic	Retinal dystrophy	2019-07-17	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376202	SCV001573258	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.14792-2A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic.
GeneDx	RCV000087007	SCV001803364	likely pathogenic	not provided	2019-07-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22025579, 30796641)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469009	SCV002766564	likely pathogenic	Usher syndrome	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.14792-2A>G 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: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.14792-2A>G has been reported in the literature in individuals affected with Usher Syndrome (examples: Vezinaw_2019 and Wafa_2021). These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001376202	SCV004173894	likely pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445508	SCV004173895	likely pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376202	SCV004207698	pathogenic	Retinitis pigmentosa 39	2024-01-19	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV000087007	SCV000119260	not provided	not provided		no assertion provided	not provided