ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.2610C>A (p.Cys870Ter) (rs767078782)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673272 SCV000798455 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-03-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826153 SCV000967688 pathogenic Usher syndrome; Rare genetic deafness 2018-07-20 criteria provided, single submitter clinical testing The p.Cys870X variant in USH2A has been previously reported in >10 probands with Usher syndrome, who were either homozygous or compound heterozygous for another USH2A variant (Baux 2017, Bonnet 2016, Comander 2017, Krawitz 2014, Le Quesne S tabej 2012, Neuhaus 2017, Sodi 2014, Weisschuh 2016). This variant has been iden tified in 0.003% (4/126016) of European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org); however, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense varia nt leads to a premature termination codon at position 870, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on t he previously reported probands with Usher syndrome, the predicted impact of the variant, and its low frequency in the general population. ACMG/AMP criteria app lied: PVS1, PM3_VeryStrong, PM2, PP4.
Blueprint Genetics RCV001075425 SCV001241048 pathogenic Retinal dystrophy 2018-08-07 criteria provided, single submitter clinical testing
Invitae RCV001384598 SCV001584154 pathogenic not provided 2020-09-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys870*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs767078782, ExAC 0.003%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22135276, 28559085). 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: 557167). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001384598 SCV001756787 pathogenic not provided 2020-04-23 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26766544, 27460420, 25333064, 25558175, 28944237, 28559085, 28981474, 22135276, 29196752)
Natera, Inc. RCV001271234 SCV001452246 pathogenic Usher syndrome, type 2A 2020-09-16 no assertion criteria provided clinical testing

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