ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.8981G>A (p.Trp2994Ter) (rs397518041)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041937 SCV000065633 pathogenic Rare genetic deafness 2010-04-02 criteria provided, single submitter clinical testing The Trp2994X variant in USH2A has been reported in 2 probands with Usher syndrom e (Yan 2009). In addition, this variant leads to a premature stop codon at posit ion 2994 and therefore, is predicted to lead to a truncated or absent protein. I n summary, this variant meets our criteria to be classified as pathogenic (http: //
Counsyl RCV000666550 SCV000790858 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-04-12 criteria provided, single submitter clinical testing
GeneDx RCV000760327 SCV000890183 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing The W2994X nonsense variant in the USH2A gene has been reported previously two patients with Usher syndrome type II; in one patient, no second variant in the USH2A gene was identified (Yan et al., 2009). The W2994X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We classify this variant as pathogenic.
Invitae RCV000760327 SCV001201117 pathogenic not provided 2019-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2994*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another USH2A variant in individuals affected with Usher syndrome or retinitis pigmentosa (PMID: PMID: 19881469, 28041643). ClinVar contains an entry for this variant (Variation ID: 48611). 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.
Blueprint Genetics RCV001075814 SCV001241450 pathogenic Retinal dystrophy 2019-07-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193386 SCV001362169 pathogenic Usher syndrome 2019-10-25 criteria provided, single submitter clinical testing Variant summary: USH2A c.8981G>A (p.Trp2994X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251094 control chromosomes (gnomAD). c.8981G>A has been reported in the literature in individuals affected with Usher syndrome and retinitis pigmentosa (e.g. Carss_2017, Stone_2017, Yan_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504790 SCV000598838 pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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