Total submissions: 24
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 |
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 | |
Ce |
RCV000814767 | SCV001246998 | pathogenic | not provided | 2019-05-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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, |
RCV000814767 | SCV001446946 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Ocular Genomics Institute, |
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, |
RCV000023700 | SCV001760014 | likely pathogenic | Usher syndrome type 2A | criteria provided, single submitter | clinical testing | ||
Gene |
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, |
RCV000814767 | SCV002020838 | pathogenic | not provided | 2021-05-14 | criteria provided, single submitter | clinical testing | |
Variantyx, |
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- |
RCV001376510 | SCV004172076 | likely pathogenic | Retinitis pigmentosa 39 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
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, |
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, |
RCV000505092 | SCV000598828 | likely pathogenic | Usher syndrome | 2015-01-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000505092 | SCV000926743 | pathogenic | Usher syndrome | 2018-04-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000787740 | SCV000926744 | pathogenic | Retinitis pigmentosa | 2018-04-01 | no assertion criteria provided | research | |
Sharon lab, |
RCV001003267 | SCV001161350 | pathogenic | Usher syndrome type 2 | 2019-06-23 | no assertion criteria provided | research | |
Natera, |
RCV000023700 | SCV001458119 | pathogenic | Usher syndrome type 2A | 2020-09-16 | no assertion criteria provided | clinical testing | |
Clinical Genetics, |
RCV000814767 | SCV001917640 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000814767 | SCV001965273 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome |
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. |