ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.8682-9A>G (rs372347027)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000710348 SCV000840545 pathogenic Usher syndrome 2018-09-24 reviewed by expert panel curation The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID: 27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PM2_Supporting, PP4, PP3.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255827 SCV000230664 likely pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000255827 SCV000321999 likely pathogenic not provided 2019-04-08 criteria provided, single submitter clinical testing In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23591405, 18273898, 25425308, 27318125, 30358468, 28944237, 31980526, 33576794)
Invitae RCV000255827 SCV001209029 pathogenic not provided 2020-11-02 criteria provided, single submitter clinical testing This sequence change falls in intron 43 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. This variant is present in population databases (rs372347027, ExAC 0.02%). This variant has been observed in several individuals with Usher syndrome type II (PMID: 23591405, 28894305, 25425308, 28944237, 18273898, 27318125). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197510). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074617 SCV001240208 pathogenic Retinal dystrophy 2019-01-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255827 SCV001246995 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000666303 SCV001573686 likely pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.8682-9A>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, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255827 SCV001762039 likely pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000710348 SCV001821355 pathogenic Usher syndrome 2021-08-05 criteria provided, single submitter clinical testing Variant summary: USH2A c.8682-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes canonical a 3 acceptor site. Two predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 250002 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (6.8e-05 vs 0.011), allowing no conclusion about variant significance. c.8682-9A>G has been reported in the literature in multiple individuals affected with Usher Syndrome and Hereditary retinal dystrophies (e.g. Glockle_2013, Zein_2014, Hartel_2016, Neuhanus_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) and likely pathogenic (n=5), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001723753 SCV001950423 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The c.8682-9A>G variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Counsyl RCV000666303 SCV000790572 likely pathogenic Retinitis pigmentosa 39 2017-04-04 no assertion criteria provided clinical testing

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