ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.1256G>T (p.Cys419Phe) (rs121912600)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224697 SCV000232370 pathogenic not provided 2016-04-21 criteria provided, single submitter clinical testing
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
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.
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.
Invitae RCV000224697 SCV001223238 pathogenic not provided 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 419 of the USH2A protein (p.Cys419Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs121912600, ExAC 0.009%). This variant has been observed in several individuals and families affected with Usher syndrome (PMID: 28041643, 24498627, 22334370, 10729113, 28559085, 24265693) and is a suspected founder mutation in the Dutch population (PMID: 15241801). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been observed to segregate with Usher syndrome in at least one family (PMID: 15043528). ClinVar contains an entry for this variant (Variation ID: 2359). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074823 SCV001240423 pathogenic Retinal dystrophy 2019-07-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224697 SCV001248863 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000778222 SCV001251480 pathogenic USH2A-Related Disorders criteria provided, single submitter research USH2A c.1256G>T (p.C419F) has been described as a pathogenic variant and has been reported in the homozygous or compound heterozygous state in multiple individuals with Usher syndrome type IIA and nonsyndromic retinitis pigmentosa (PMID: 15015129; 15241801;15325563; 10729113; 22135276; 24944099; 25999674).
Integrated Genetics/Laboratory Corporation of America RCV000504809 SCV001362170 pathogenic Usher syndrome 2019-12-09 criteria provided, single submitter clinical testing Variant summary: USH2A c.1256G>T (p.Cys419Phe) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250184 control chromosomes. c.1256G>T has been reported in the literature in multiple individuals affected with Usher syndrome and/or Retinitis Pigmentosa (example, Weston_2000, Neveling_2012, Eisenberger_2013, Stone_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000002453 SCV000022611 pathogenic Usher syndrome, type 2A 2004-04-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504809 SCV000598775 uncertain significance Usher syndrome 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000002453 SCV000804732 pathogenic Usher syndrome, type 2A 2016-09-01 no assertion criteria provided clinical testing
Counsyl RCV000002453 SCV001132499 pathogenic Usher syndrome, type 2A 2017-02-08 no assertion criteria provided clinical testing
Counsyl RCV000984315 SCV001132500 pathogenic Retinitis pigmentosa 39 2017-02-08 no assertion criteria provided clinical testing

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