rs80338902
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. BS1PP4PP3PS4PM3_StrongPP1_Strong
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA252233/MONDO:0019501/005
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 5 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 5.53
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| USH2A | NM_206933.4 | c.2276G>T | p.Cys759Phe | missense_variant | 13/72 | ENST00000307340.8 | NP_996816.3 | |
| USH2A | NM_007123.6 | c.2276G>T | p.Cys759Phe | missense_variant | 13/21 | NP_009054.6 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| USH2A | ENST00000307340.8 | c.2276G>T | p.Cys759Phe | missense_variant | 13/72 | 1 | NM_206933.4 | ENSP00000305941 | P1 | |
| USH2A | ENST00000366942.3 | c.2276G>T | p.Cys759Phe | missense_variant | 13/21 | 1 | ENSP00000355909 | |||
| USH2A | ENST00000674083.1 | c.2276G>T | p.Cys759Phe | missense_variant | 13/73 | ENSP00000501296 |
Frequencies
GnomAD3 genomes 0.00131 AC: 199AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000969 AC: 243AN: 250722Hom.: 0 AF XY: 0.000893 AC XY: 121AN XY: 135474
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GnomAD4 genome 0.00131 AC: 199AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102AN XY: 74418
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:46Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 31, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 759 of the USH2A protein (p.Cys759Phe). This variant is present in population databases (rs80338902, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive isolated retinitis pigmentosa and USH2A-related disorders (PMID: 10775529, 12525556, 15325563, 25649381, 25910913, 28041643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2356). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 04, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | USH2A: PM3:Very Strong, PM2:Supporting, PS3:Supporting - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 05, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2024 | Published functional studies using a zebrafish knock-in model suggest a damaging effect with decreased expression of usherin and impaired visual function (PMID: 35672333); 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: 25472526, 29588463, 33576794, 33105617, 12525556, 25097241, 20440071, 30609409, 30245029, 30924848, 32483926, 31429209, 32531858, 25262649, 10775529, 25910913, 26764160, 25649381, 26969326, 22004887, 15325563, 29283788, 28678594, 30390570, 32581362, 25326637, 28838317, 30190494, 28559085, 32050993, 32176120, 29953849, 24963352, 29777677, 28041643, 30081015, 29431110, 30337596, 32036094, 14970843, 30096711, 28945494, 34327195, 34426522, 33302505, 33089500, 32037395, 35836572, 34948090, 36051698, 36003347, 36034145, 36140798, 36011334, 34599368, 34781295, 35266249, 31877679, 35672333, 25823529, 29912909) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Retinitis pigmentosa 39 Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Feb 05, 2013 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 12, 2021 | PS1, PS4, PP3, PP4, PM3 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 03, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.097%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10909849 , 12112664 , 12525556 , 14970843 , 15325563 , 16098008 , 17405132 , 18273898 , 19683999 , 21151602 , 21738395 , 22004887 , 22135276 , 22334370 , 23591405 , 24944099 , 25097241 , 25261458 , 25262649 , 25375654 , 25649381 , 25823529 , 25910913 , 26764160 , 28041643 , 29283788 , 29588463). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 29912909). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 16, 2023 | This variant was identified as compound heterozygous with NM_206933.4:c.12698G>A._x000D_ Criteria applied: PS4, PM3_STR, PP1, PP3 - |
Usher syndrome type 2A Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 17, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (RP; MIM# 6138093). Null variants are associated with Usher syndrome while homozygous missense which lead to partially functional proteins typically cases non-syndromic RP (PMID: 20301515). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 273 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Laminin EGF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple Usher syndrome and RP individuals and classified as pathogenic by ClinGen’s hearing loss expert panel. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 07, 2024 | Criteria applied: PM3_VSTR,PP1_STR,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Retinitis pigmentosa Pathogenic:4Other:1
| Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | research | Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Jul 24, 2023 | Clinical significance based on ACMG v2.0 - |
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | 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. - |
Usher syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 28, 2019 | The p.Cys759Phe variant in USH2A is a common pathogenic variant reported in 21 individuals with Usher syndrome and 90 individuals with isolated recessive retinitis pigmentosa (Rivolta 2000, Dreyer 2000, Najera 2002, Rivolta 2002, Bernal 2003, Aller 2004, Seyedahmadi 2004, Bernal 2005, Baux 2007, Dreyer 2008, Sandberg 2008, Avila-Fernandez 2010, Vozzi 2011). It has also been identified in 0.2% (72/35410) of Latino chromosomes and 0.1% (182/128602) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is consistent with a recessive carrier frequency. This variant has also been reported by several clinical laboratories in ClinVar as pathogenic or likely pathogenic (Variation ID 2356). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant is commonly seen with a second pathogenic allele and is observed to cosegregate with disease in affected family members. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type IIA and retinitis pigmentosa both in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_Strong, PP1_Strong, PP3, PP4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2019 | 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. - |
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jul 28, 2019 | 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 w - |
Retinal dystrophy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 30, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 15, 2021 | The USH2A c.2276G>T variant is classified as Pathogenic (PS4, PM3_Strong, PP1, PP3) The USH2A c.2276G>T variant is a single nucleotide change in the USH2A gene, which is predicted to change the amino acid cysteine at position 759 in the protein to phenylalanine. The variant has been reported in probands with a clinical presentation of Retinal dystrophy (PS4). PMID: 29912909. This variant segregates with disease in multiple unrelated families with Usher syndrome type II and non-syndromic ARRP (Pérez-Carro et al., 2018, PMID:29912909, Rivolta et al., 2000, PMID:10775529, Bernal at al, 2003, PMID:12525556, Ávila-Fernández et al., 2010, PMID:21151602) (PP1). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). Cysteine at position 759 is highly conserved (PhyloP=5.53) located in the EGF-like, laminin domain. Substitution with Phenylalanine is a non-conservative change (Grantham Score =205). Computational analysis predicts this change is damaging (CADD=33, SIFT=Deleterious). The variant has been reported in dbSNP (rs80338902) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2356). - |
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
USH2A-related disorder Pathogenic:2Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | 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; Ãvila-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; Ãvila-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. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | The USH2A c.2276G>T variant is predicted to result in the amino acid substitution p.Cys759Phe. This variant has been reported many times in individuals with autosomal recessive Usher syndrome or non-syndromic retinitis pigmentosa (see for examples Rivolta et al. 2000. PubMed ID: 10775529; Aller et al. 2004. PubMed ID: 14970843; Garcia-Garcia et al. 2011. PubMed ID: 22004887). Several other missense variants occurring within amino acids 761 to 768 of USH2A have been reported as causative for Usher syndrome type 2, suggesting that this protein domain plays an important functional role (Bernal et al. 2003. PubMed ID: 12525556; Glöckle et al. 2014. PubMed ID: 23591405; Piearrche et al. 2016. PubMed ID: 26927203). This variant is reported in 0.20% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/2356/). This variant is interpreted as pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Likely pathogenic and reported on 05-24-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2015 | - - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | Sep 10, 2015 | - - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 10, 2020 | ACMG classification criteria: PS4, PM3, PP1, PP3 - |
Ear malformation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at