Submissions for variant NM_206933.4(USH2A):c.11048-2A>G

gnomAD frequency: 0.00002  dbSNP: rs200871041

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821987	SCV000962764	pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 553421). 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. Disruption of this splice site has been observed in individuals with Usher syndrome or severe hearing loss (PMID: 28944237, 28984810; Invitae). This variant is present in population databases (rs200871041, gnomAD 0.002%). This sequence change affects an acceptor splice site in intron 56 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	RCV001074654	SCV001240246	likely pathogenic	Retinal dystrophy	2019-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000821987	SCV001246249	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810473	SCV002060192	pathogenic	Usher syndrome type 2A	2021-11-11	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.11048-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.11048-2A>G has been observed in cases with relevant disease (PMID: 32531858, 28944237, 28984810, 30358468, 31370859). Functional assessments of this variant are not available in the literature. c.11048-2A>G has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, NM_206933.2(USH2A):c.11048-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002468597	SCV002765077	pathogenic	Retinitis pigmentosa 39	2022-11-24	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PM3, PM2_SUP
GeneDx	RCV000821987	SCV003936387	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31370859, 28944237, 32531858)
Genome-Nilou Lab	RCV002468597	SCV004172006	likely pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001810473	SCV004172007	likely pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002468597	SCV004208395	pathogenic	Retinitis pigmentosa 39	2024-03-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001810473	SCV002088340	pathogenic	Usher syndrome type 2A	2020-06-09	no assertion criteria provided	clinical testing