ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.1256G>T (p.Cys419Phe) (rs121912600)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224697 SCV000281626 pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224697 SCV000232370 pathogenic not provided 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000224697 SCV000583303 pathogenic not provided 2018-12-13 criteria provided, single submitter clinical testing The C419F variant in the USH2A gene has been reported previously in association with Usher syndrome type II and non-syndromic retinitis pigmentosa when present in the homozygous state or in trans with another disease-causing variant (Weston et al., 2000; Pennings et al., 2004; Le Quesne et al., 2012; Baux et al., 2014). The C419F variant is observed in 6/64726 (0.0093%) alleles from individuals of European background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C419F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C419F as a pathogenic variant.
Human Genetics - Radboudumc,Radboudumc RCV000002453 SCV000804732 pathogenic Usher syndrome, type 2A 2016-09-01 no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778222 SCV000914388 pathogenic USH2A-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing Across a selection of the available literature, the USH2A c.1256G>T (p.Cys419Phe) missense variant has been identified in a homozygous state in two patients with Usher syndrome, in a compound heterozygous state in 13 patients of whom ten were diagnosed with Usher syndrome and three with retinitis pigmentosa (RP), and in a heterozygous state in 16 patients of whom ten were diagnosed with Usher syndrome and six with RP (Weston et al. 2000; Van Wijk et al. 2004; Seyedahmadi et al. 2004; Sandberg et al. 2008; Neveling et al. 2012; Le Quesne Stabe et al. 2012; Eisenberger et al. 2013; Besnard et al. 2014; Cremers et al. 2014; Pennings et al. 2004; Van Huet et al. 2015). The p.Cys419Phe variant is a possible Dutch founder variant as deduced by haplotype analysis by Pennings et al. (2004). The p.Cys419Phe variant was absent in at least 1000 controls and is reported at a frequency of 0.000093 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Cys419Phe variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824795 SCV000065420 pathogenic Rare genetic deafness 2010-10-28 criteria provided, single submitter clinical testing The Cys419Phe variant in USH2A has been reported in 16/246 probands with Usher s yndrome Type 2 and was absent from 380 control chromosomes (p<0.0001, Weston 200 0, Pennings 2004, Seyedahmadi 2004). Many of these probands were homozygous or c ompound heterozygous. In addition, this variant is thought to be a founder mutat ion in the Dutch population (Pennings 2004). In summary, this variant meets our criteria to be classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504809 SCV000598775 uncertain significance Usher syndrome 2015-01-01 no assertion criteria provided research
OMIM RCV000002453 SCV000022611 pathogenic Usher syndrome, type 2A 2004-04-01 no assertion criteria provided literature only

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