ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.7595-2144A>G (rs786200928)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664608 SCV000788602 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-04-28 criteria provided, single submitter clinical testing
Invitae RCV000814767 SCV000955192 pathogenic not provided 2020-10-13 criteria provided, single submitter clinical testing This sequence change falls in intron 40 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed to segregate with Usher syndrome in several families (PMID: 22009552, 23924366). ClinVar contains an entry for this variant (Variation ID: 30722). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22009552). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074209 SCV001239782 pathogenic Retinal dystrophy 2019-03-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000814767 SCV001246998 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505092 SCV001442777 pathogenic Usher syndrome 2020-10-30 criteria provided, single submitter clinical testing Variant summary: USH2A c.7595-2144A>G is reported in the literature to induce activation of a pseudoexon, predicted to result in a frameshift of the protein (e.g. Vache_2011). Several computational tools predict a significant impact on normal splicing: Four predict that the variant creates a new 5' donor site. The variant allele was found at a frequency of 6.4e-05 in 31406 control chromosomes. c.7595-2144A>G has been reported in the literature in multiple individuals affected with Usher Syndrome, including evidence for cosegregation with disease in several families (e.g. Vache_2011, Steele-Stallard_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant activates a pseudoexon, resulting in aberrant splicing (e.g. Vache_2011). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000814767 SCV001446946 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376510 SCV001573685 likely pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.7595-2144A>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: PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Genomics England Pilot Project,Genomics England RCV000023700 SCV001760014 likely pathogenic Usher syndrome, type 2A criteria provided, single submitter clinical testing
GeneDx RCV000814767 SCV001780430 pathogenic not provided 2019-10-31 criteria provided, single submitter clinical testing Observed with a second USH2A variant in multiple individuals with Usher syndrome in the published literature, however, the phase of these variants is unknown (Sodi et al., 2018; Khalaileh et al., 2018; Steele-Stallard et al., 2013); Non-canonical splice site variant demonstrated to result in loss-of-function; functional studies demonstrated an insertion of 152 bp at the junction of exons 40 and 41, leading to an out-of-frame protein with premature stop codon in exon 41 (designated p.K2532TfsX56) (Vache et al., 2012; Steele-Stallard et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33576794, 32581362, 31980526, 31456290, 27460420, 25558175, 29490346, 22009552, 25352746, 23924366, 28041643, 25823529, 25649381, 27802265, 30281416, 26629787, 25404053, 31231422, 30718709)
OMIM RCV000023700 SCV000044991 pathogenic Usher syndrome, type 2A 2012-01-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505092 SCV000598828 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000505092 SCV000926743 pathogenic Usher syndrome 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787740 SCV000926744 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003267 SCV001161350 pathogenic Usher syndrome type 2 2019-06-23 no assertion criteria provided research
Natera, Inc. RCV000023700 SCV001458119 pathogenic Usher syndrome, type 2A 2020-09-16 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000814767 SCV001917640 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000814767 SCV001956545 pathogenic not provided no assertion criteria provided clinical testing

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