ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) (rs80338902)

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Total submissions: 35
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000505146 SCV001334331 pathogenic Usher syndrome 2019-07-28 reviewed by expert panel curation The p.Cys759Phe variant in USH2A has been reported in 10 individuals with a clinical diagnosis of Usher Syndrome type II who were all confirmed compound heterozygous with a second pathogenic variant on the remaining allele (PMIDs: 16098008, 24944099, 29912909) (PM3_Strong). Note that scoring for PM3 was downgraded from PM3_VeryStrong to PM3_Strong since this variant has an allele frequency that meets criteria for BS1 (see below). Co-segregation with Usher II was demonstrated collectively in 2 affected and 13 unaffected siblings (LOD score: 2.23). When including all families affected with Usher II or an atypical Usher presentation (retinitis pigmentosa (RP) with some form of hearing loss), co-segregation can be identified in three affected and 26 unaffected siblings total (LOD score: 4.45) (PMID: 29912909) (PP1_Strong). When considering those patients who present with isolated RP, the variant segregated in an additional 15 affected and 32 unaffected siblings (LOD score: 12.43) (PMIDs:10775529, 12525556, 21151602, 29912909). The filtering allele frequency (the lower threshold of the 95% CI of 72/35410) of the p.Cys759Phe variant in the Latino population in gnomAD is 0.17% and it has also been observed at the filtering allele frequency (the lower threshold of the 95% CI of 17/2536) of 0.43% across several Spanish or Latino populations published in the literature (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529; BS1). Although this allele frequency meets the threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants, other studies suggest it may still be associated with Usher syndrome, albeit with potentially reduced penetrance. The variant is statistically enriched in cohorts of Usher (2.00% (54/2704) in Usher patients compared to 0.67% (17/2536) as the highest and most ethnically matched published Spanish and Latino control populations; Fisher's exact p value <0.0001) and RP patients (1.87% (109/5828) in RP patients compared to 0.71% in published Spanish and Latino controls; Chi-Square p value <0.0001) (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529, 10909849, 12112664, 14970843, 15325563, 16098008, 17405132, 18273898, 19683999, 22004887, 21738395, 24944099, 25375654, 28041643, 29588463, 21151602, 25097241, 23591405, 25910913, 25649381, 29283788, 22135276, 22334370) (PS4). The association with Usher syndrome is particularly clear when paired with a predicted loss-of-function or other pathogenic variant compared to homozygous individuals who are more at risk to develop non-syndromic RP (PMIDs: 29912909 and 25375654). There may also be evidence of reduced penetrance for both hearing loss and RP as two homozygous individuals were documented to have no evidence of any phenotype through their 6th decade (PMIDs: 16098008, 12525556). The PP4 rule has also been applied to this variant given the combination of hearing loss and RP that is seen in these patients and that most patients were screened for other Usher genes. Lastly, computational prediction tools and conservation analysis suggest that the p.Cys759Phe variant may impact the protein (REVEL: 0.902), and an analysis using the homologous mouse laminin gamma 1 chain concluded that this variant is likely to disrupt disulfide bonding with the cysteine at position 747 (PMID: 10909849) (PP3). In summary, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Usher Syndrome outweighs its higher than expected allele frequency in population databases and other general population cohorts. Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome (ACMG codes applied: BS1, PS4, PM3_Strong, PP1_Strong, PP4, and PP3). Please note that patients with this variant may present with either Usher syndrome or with isolated RP. Isolated RP presentations are more common when the variant is seen in homozygosity as opposed to combined with a distinct pathogenic USH2A variant.
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
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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 RCV000002450 SCV000487439 likely pathogenic Retinitis pigmentosa 39 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000239000 SCV000616913 pathogenic not provided 2021-08-31 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25823529, 20440071, 33105617, 33576794, 29912909, 32036094, 32176120, 32050993, 28559085, 30337596, 30190494, 29431110, 30081015, 29777677, 24963352, 29953849, 28838317, 25326637, 28945494, 28041643, 30096711, 14970843, 26764160, 32581362, 30245029, 25097241, 28678594, 29283788, 29588463, 15325563, 25472526, 22004887, 26969326, 25649381, 25910913, 10775529, 25262649, 12525556, 30390570, 30609409, 30924848)
Ambry Genetics RCV000623925 SCV000740835 pathogenic Inborn genetic diseases 2015-03-03 criteria provided, single submitter clinical testing
Invitae RCV000239000 SCV000931893 pathogenic not provided 2020-11-01 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.
Mendelics RCV000174625 SCV001135564 likely pathogenic Usher syndrome, type 2A 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000174625 SCV001162882 pathogenic Usher syndrome, type 2A criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000174625 SCV001194111 likely pathogenic Usher syndrome, type 2A 2019-12-17 criteria provided, single submitter clinical testing NM_206933.2(USH2A):c.2276G>T(C759F) is classified as likely pathogenic in the context of USH2A-related disorders and is associated with variable presentation of this disease. Sources cited for classification include the following: PMID 24944099, 1968399 and 18273898. Classification of NM_206933.2(USH2A):c.2276G>T(C759F) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics RCV000504814 SCV001239951 pathogenic Retinal dystrophy 2019-07-30 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000174625 SCV001244815 pathogenic Usher syndrome, type 2A 2020-02-05 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_206933.3(USH2A):c.2276G>T in exon 13 of 72 of the USH2A gene. This substitution is predicted to create a major amino acid change from cysteine to phenylalanine at position 759 of the protein, NP_996816.2(USH2A):p.(Cys759Phe). The cysteine at this position has high conservation (100 vertebrates, UCSC), and is located within the Laminin EGF-like 5 domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.097% (273 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in multiple families with retinitis pigmentosa and Usher syndrome (ClinVar, Perez-Carro, R. et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000239000 SCV001248859 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505146 SCV001362168 pathogenic Usher syndrome 2019-11-26 criteria provided, single submitter clinical testing Variant summary: USH2A c.2276G>T (p.Cys759Phe) results in a non-conservative amino acid change located in the Laminin EGF-like 5 domain 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 0.00097 in 250722 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher syndrome (0.00097 vs 0.013), allowing no conclusion about variant significance. c.2276G>T has been reported in the literature in multiple individuals affected with nonsyndromic RP, Usher Syndrome and atypical Usher syndrome (e.g. Rivolta_2000, Aller_2004). 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. Twelve ClinVar submissions (evaluation after 2014) cite the variant eight times as pathogenic and four times as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000239000 SCV001446852 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285994 SCV001472509 likely pathogenic none provided 2020-01-10 criteria provided, single submitter clinical testing The USH2A c.2276G>T; p.Cys759Phe variant (rs80338902) is reported in the medical literature in the homozygous or compound heterozygous state in individuals with retinal disease (Bernal 2003, Carss 2017, Lenassi 2015, Seyedahmadi 2004) and is reported to segregate with disease (Rivolta 2000). The variant is reported to occur at an increased frequency compared to control individuals (Seyedahmadi 2004). However, the variant was also detected in two unaffected individuals in the homozygous state (Bernal 2003). The variant is reported as pathogenic or likely pathogenic for Usher-related disease by several sources in the ClinVar database (Variation ID: 2356); however, the variant was recently classified as a variant of uncertain significance for hearing loss based on an expert panel curation (Azaiez 2018). The variant is reported in the general population with an overall allele frequency of 0.097% (273/282,114 alleles) in the Genome Aggregation Database. The cysteine at codon 759 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Azaiez H et al. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet. 2018 Oct 4;103(4):484-497. Bernal S et al. Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation. J Med Genet. 2003 Jan;40(1):e8. Carss KJ et al. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017 Jan 5;100(1):75-90. Lenassi E et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27 Rivolta C et al. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000 Jun;66(6):1975-8. Seyedahmadi BJ et al. Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004 Aug;79(2):167-73.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000002450 SCV001573414 likely pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.2276G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Nilou-Genome Lab RCV000174625 SCV001737166 pathogenic Usher syndrome, type 2A 2021-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000002450 SCV001934219 pathogenic Retinitis pigmentosa 39 2020-10-06 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000032523 SCV001950411 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Cys759Phe variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
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
Faculty of Health Sciences,Beirut Arab University RCV001257905 SCV001434721 pathogenic Autosomal recessive retinitis pigmentosa 2015-09-10 no assertion criteria provided literature only
GenomeConnect - Invitae Patient Insights Network RCV001535506 SCV001749461 not provided Usher syndrome, type 2A; Retinitis pigmentosa 39 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-01-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000239000 SCV001807717 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000239000 SCV001920751 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000239000 SCV001955128 likely pathogenic not provided no assertion criteria provided clinical testing

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