ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.1876C>T (p.Arg626Ter) (rs534534437)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000599059 SCV000701902 pathogenic not provided 2016-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000599059 SCV000709899 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The R626X nonsense variant in the USH2A gene has been reported previously in the homozygous and compound heterozygous states in association with Usher syndrome (Weston et al., 2000; Ouyang et al., 2004; Syedahmadi et al., 2004; Xu et al., 2011; Jiang et al., 2015; Bonnet et al., 2016). This variant was observed multiple times with a pathogenic variant in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R626X variant is observed in 5/111594 (0.0045%) alleles from individuals of European (non-Finnish) background, in the ExAC dataset (Lek et al., 2016). Based on currently available evidence, we consider R626X to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000592080 SCV000710847 pathogenic Usher syndrome 2019-03-19 criteria provided, single submitter clinical testing The p.Arg626X variant in USH2A has been reported >15 individuals with Usher syndrome, at least 9 of whom were homozygous or compound heterozygous with a second pathogenic USH2A variant on the other allele, and segregated in the compound heterozygous state in one affected relative (Weston 2000, Ouyang 2004, Seyedahmadi 2004, Ebermann 2009, Xu 2011, Jiang 2015, Lenassi 2015, Bonnet 2016). This variant has also been identified in 0.006% (7/113672) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 626, which is predicted to lead to a truncated or absent protein. Loss of function of the USH2A gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic USH2A variants in individuals with Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1, PM2, PP1.
Invitae RCV000599059 SCV000959652 pathogenic not provided 2019-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg626*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs534534437, ExAC 0.001%). This variant has been observed in several individuals affected with USH2A-related conditions (PMID: 10729113, 21686329, 15823922, 25649381). ClinVar contains an entry for this variant (Variation ID: 497414). 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 RCV001074303 SCV001239876 pathogenic Retinal dystrophy 2019-06-19 criteria provided, single submitter clinical testing

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