ClinVar Miner

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

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Total submissions: 24
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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
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 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 2020-01-15 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
Integrated Genetics/Laboratory Corporation of America 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.
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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