ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.2276G>T (p.Cys759Phe) (rs80338902)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000505146 SCV000065507 pathogenic Usher syndrome 2018-02-14 criteria provided, single submitter clinical testing The p.Cys759Phe variant in USH2A is a common pathogenic variant reported in 21 i ndividuals with Usher syndrome and 90 individuals with isolated recessive retini tis pigmentosa (Rivolta 2000, Dreyer 2000, Najera 2002, Rivolta 2002, Bernal 200 3, Aller 2004, Seyedahmadi 2004, Bernal 2005, Baux 2007, Dreyer 2008, Sandberg 2 008, Avila-Fernandez 2010, Vozzi 2011). It has also been identified in 0.1% (67/ 66700) of European chromosomes and 0.2% (22/11552) Latino chromosomes by the Exo me Aggregation Consortium (http://exac.broadinstitute.org/; dbSNP rs80338902); h owever, this frequency is consistent with a recessive carrier frequency. Additio nally, this variant is commonly seen with a second pathogenic allele and is obse rved to cosegregate with disease in affected family members. In summary, this va riant meets our criteria to be classified as pathogenic for Usher syndrome type IIA and retinitis pigmentosa both in an autosomal recessive manner.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000239000 SCV000225954 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000002450 SCV000255503 likely pathogenic Retinitis pigmentosa 39 2013-02-05 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239000 SCV000297411 pathogenic not provided 2015-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404009 SCV000354148 pathogenic USH2A-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.2276G>T (p.Cys759Phe) variant is a well described pathogenic variant for USH2A-related disorders. Across a selection of the available literature, the variant is reported in over 90 patients with retinitis pigmentosa and 40 patients with Usher syndrome (Rivolta et al. 2000; Dreyer et al. 2000; Nájera et al. 2002; Rivolta et al. 2002; Bernal et al. 2003; Aller et al. 2004; Seyedahmadi et al. 2004; Bernal et al. 2005; Baux et al. 2007; Dreyer et al. 2008; Sandberg et al. 2008; Ávila-Fernández et al. 2010; Vozzi et al. 2011; Glöckle et al. 2014; Blanco-Kelly et al. 2015; Lenassi et al. 2015). Among those with isolated retinitis pigmentosa, fifteen were found to be homozygous for the variant and 34 were identified as compound heterozygous for the variant. Furthermore, the p.Cys759Phe variant has been found to cosegregate with disease in multiple families (Bernal et al. 2003; Ávila-Fernández et al. 2010). The variant was identified in a heterozygous state in eight of 3400 controls, and is reported at a frequency of 0.00209 in the European American population of the Exome Sequencing Project. The Cys759 residue occurs in a laminin-type epidermal growth factor-like domain. The p.Cys759Phe variant is predicted to disrupt disulfide bond formation and lead to abnormal protein folding (Dreyer et al. 2000; Baux et al. 2007). Based on the collective evidence, the p.Cys759Phe variant is classified as pathogenic for USH2A-related disorders.
Counsyl RCV000174625 SCV000487438 likely pathogenic Usher syndrome, type 2A 2016-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000002450 SCV000487439 likely pathogenic Retinitis pigmentosa 39 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000239000 SCV000616913 likely pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The C759F variant in the USH2A gene has been reported previously in the either the homozygous or compound heterozygous state in multiple unrelated individuals with retinitis pigmentosa (Rivolta et al., 2000; Bernal et al., 2003; Lenassi et al., 2015; Perez-Carro et al., 2018). However, the C759F variant has also been observed in the homozygous state in a few unaffected individuals as well as in affected individuals who harbor variants in other retinitis pigmentosa associated genes (Bernal et al., 2003; Wang et al., 2014; Pozo et al., 2015). The C759F variant is observed in 69/34,392 (0.2%) alleles from individuals of Latino background and in 262/276,470 (0.095%) global alleles in large population cohorts (Lek et al., 2016). The C759F variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C759F as a likely pathogenic variant.
Ambry Genetics RCV000623925 SCV000740835 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 RCV000239000 SCV000931893 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 759 of the USH2A protein (p.Cys759Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs80338902, ExAC 0.2%). This variant has been reported to segregate with autosomal recessive isolated retinitis pigmentosa in several families (PMID: 10775529, 12525556) and has been reported in the homozygous or compound heterozygous state in many individuals affected with USH2A-related disorders (PMID: 15325563, 25910913, 25649381, 28041643). ClinVar contains an entry for this variant (Variation ID: 2356). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002450 SCV000022608 pathogenic Retinitis pigmentosa 39 2015-07-01 no assertion criteria provided literature only
GeneReviews RCV000032523 SCV000056186 pathologic Retinitis pigmentosa 2010-12-23 no assertion criteria provided curation Converted during submission to Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000032523 SCV000598796 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505146 SCV000598797 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504814 SCV000598798 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000002450 SCV000804739 likely pathogenic Retinitis pigmentosa 39 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000032523 SCV000926728 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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