ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.9424G>T (p.Gly3142Ter) (rs397518048)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041952 SCV000065648 pathogenic Usher syndrome; Rare genetic deafness 2018-07-20 criteria provided, single submitter clinical testing The p.Gly3142X variant has been reported in 9 individuals with Usher syndrome, 4 patients with retinal dystrophy, and 1 patient with sensorineural hearing loss, and at least 10 of these individuals were compound heterozygous for a second pa thogenic USH2A variant (Baux 2007, Sandberg 2008, McGee 2010, Glockle 2013, Kraw itz 2014, Baux 2014, Lenarduzzi 2015, Lenassi 2015, Bonnet 2016, LMM data). This variant was identified in 0.005% (5/110538) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, thi s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 3142, wh ich is predicted to lead to a truncated or absent protein. In summary, this vari ant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, the reported compound het erozygous individuals with Usher syndrome, and its low frequency in the general population. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PM2, PP4.
Ambry Genetics RCV000624783 SCV000740836 pathogenic Inborn genetic diseases 2015-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV001055909 SCV001220324 pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly3142*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397518048, ExAC 0.006%). This variant has been observed to segregate with inherited retinal degeneration in a family (PMID: 28130426). In addition, this variant has been observed in several individuals affected with Usher syndrome (PMID: 17405132, 28653555, 23591405). ClinVar contains an entry for this variant (Variation ID: 48626). ClinVar contains an entry for this variant (Variation ID: 48626). 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 RCV001074810 SCV001240408 pathogenic Retinal dystrophy 2019-07-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001055909 SCV001246990 pathogenic not provided 2018-12-01 criteria provided, single submitter clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003263 SCV001161346 pathogenic Usher syndrome type 2 2019-06-23 no assertion criteria provided research

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