ClinVar Miner

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

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Total submissions: 7
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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 (, 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 2017-02-21 criteria provided, single submitter clinical testing The c.8682-9 A>G splice site variant has been previously reported and was predicted to be a benign variant (Dreyer et al., 2008). However, one out of three in-silico splice prediction algorithms predicted that the c.8682-9 A>G variant results in the creation of a weak cryptic acceptor splice site. More recently, the c.8682-9 A>G variant has been reported in an individual with sporadic Usher syndrome in trans with a second USH2A variant, as confirmed in his unaffected parents who were carriers (Glockle et al., 2014). In addition, this variant has been seen previously at GeneDx to co-segregate with an Usher syndrome type 2A phenotype in a large family. The c.8682-9 A>G variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. An additional splice site variant affecting intron 43 has been reported in the Human Gene Mutation Database in association with Usher syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded.
Invitae RCV000255827 SCV001209029 likely pathogenic not provided 2019-11-20 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Counsyl RCV000666303 SCV000790572 likely pathogenic Retinitis pigmentosa 39 2017-04-04 no assertion criteria provided clinical testing

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