ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.7595-2144A>G

gnomAD frequency: 0.00004  dbSNP: rs786200928
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Total submissions: 24
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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
Labcorp Genetics (formerly Invitae), Labcorp RCV000814767 SCV000955192 pathogenic not provided 2024-01-08 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs786200928, gnomAD 0.007%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22009552, 23924366). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30722). Studies have shown that this variant results in an insertion of 152bp at the junction of exons 40 and 41 and introduces a premature termination codon (PMID: 22009552). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Center for Human Genetics 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 2022-03-07 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); This variant is associated with the following publications: (PMID: 25404053, 33576794, 31980526, 31456290, 32581362, 31231422, 30718709, 26629787, 23924366, 30281416, 27802265, 25649381, 25823529, 28041643, 22009552, 25352746, 29490346, 25558175, 27460420, 32037395)
Revvity Omics, Revvity RCV000814767 SCV002020838 pathogenic not provided 2021-05-14 criteria provided, single submitter clinical testing
Variantyx, Inc. RCV001824575 SCV002754525 pathogenic USH2A-related disorder 2022-11-07 criteria provided, single submitter clinical testing This is a non-canonical splice variant in the USH2A gene (OMIM 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. This variant causes a splicing defect that results in retention of a 152-bp intronic segment at the junction of exons 40 and 41 (PMID: 22009552). This event introduces a premature stop codon and results in loss of function, which is a known disease mechanism for USH2A (PMID: 20507924) (PVS1). This variant has been observed in the homozygous or compound heterozygous state in several affected individuals, including evidence of segregation with disease in at least two families (PMID: 22009552, 23924366) (PP1_Moderate). This variant has a 0.01928% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/), which is lower than expected for the prevalence of USH2A-related disease (PM2_Supporting). Based on current evidence, this variant is classified as pathogenic for autosomal recessive USH2A-related disorders.
Genome-Nilou Lab RCV001376510 SCV004172076 likely pathogenic Retinitis pigmentosa 39 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000023700 SCV004172077 likely pathogenic Usher syndrome type 2A 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV001376510 SCV004207691 pathogenic Retinitis pigmentosa 39 2024-03-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017262 SCV004847503 pathogenic Rare genetic deafness 2017-11-07 criteria provided, single submitter clinical testing 7595-2144A>G variant in USH2A has been reported in 9 individuals with USH2A in compound heterozygous state with another pathogenic USH2A allele, of which 6 were confirmed to occur in trans, segregated in 6 affected relatives and absent from 518 control chromosomes (Vache 2012). RNA samples from these patients showed abnormal splicing predicted to lead to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, low frequency in the general population, and observed deleterious impact on splicing.
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
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000505092 SCV000926743 pathogenic Usher syndrome 2018-04-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, 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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000814767 SCV001965273 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV001824575 SCV002074877 not provided USH2A-related disorder no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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