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rs80338902

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_206933.4(USH2A):c.2276G>T(p.Cys759Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00146 in 1,614,038 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

14
3
2

Clinical Significance

Pathogenic reviewed by expert panel P:45O:3

Conservation

PhyloP100: 5.53
Variant links:
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 12 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_206933.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897
PP5
Variant 1-216247118-C-A is Pathogenic according to our data. Variant chr1-216247118-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2356.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-216247118-C-A is described in Lovd as [Pathogenic]. Variant chr1-216247118-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-216247118-C-A is described in Lovd as [Pathogenic]. Variant chr1-216247118-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.2276G>T p.Cys759Phe missense_variant 13/72 ENST00000307340.8
USH2ANM_007123.6 linkuse as main transcriptc.2276G>T p.Cys759Phe missense_variant 13/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.2276G>T p.Cys759Phe missense_variant 13/721 NM_206933.4 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.2276G>T p.Cys759Phe missense_variant 13/211 O75445-2
USH2AENST00000674083.1 linkuse as main transcriptc.2276G>T p.Cys759Phe missense_variant 13/73 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00131
AC:
199
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00315
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00181
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000969
AC:
243
AN:
250722
Hom.:
0
AF XY:
0.000893
AC XY:
121
AN XY:
135474
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00205
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00140
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00148
AC:
2158
AN:
1461782
Hom.:
5
Cov.:
31
AF XY:
0.00142
AC XY:
1029
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00177
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00178
Gnomad4 OTH exome
AF:
0.00151
GnomAD4 genome
AF:
0.00131
AC:
199
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.00137
AC XY:
102
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.000529
Gnomad4 AMR
AF:
0.00314
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00181
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00138
Hom.:
1
Bravo
AF:
0.00149
TwinsUK
AF:
0.00189
AC:
7
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00209
AC:
18
ExAC
AF:
0.000782
AC:
95
EpiCase
AF:
0.00169
EpiControl
AF:
0.00119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:45Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 05, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 09, 2023The 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 submitterclinical testingRevvity Omics, RevvitySep 04, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaOct 31, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 02, 2023In 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, 25823529, 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, 29912909, 34327195, 34426522, 33302505, 33089500, 32037395, 35836572, 34948090, 36051698, 36003347, 36034145, 36140798, 36011334, 35672333, 34599368, 34781295, 35266249, 31877679) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2022- -
Retinitis pigmentosa 39 Pathogenic:10
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The 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. -
Likely pathogenic, criteria provided, single submitterclinical testingUCLA Clinical Genomics Center, UCLAFeb 05, 2013- -
Likely pathogenic, criteria provided, single submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The 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 submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJul 12, 2021PS1, PS4, PP3, PP4, PM3 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 16, 2023This variant was identified as compound heterozygous with NM_206933.4:c.12698G>A._x000D_ Criteria applied: PS4, PM3_STR, PP1, PP3 -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 21, 2020A 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, Pérez-Carro, R. et al . (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylNov 03, 2016- -
Likely pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+Sep 01, 2016- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2015- -
Usher syndrome type 2A Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 23, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 07, 2024Criteria applied: PM3_VSTR,PP1_STR,PP3 -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 17, 2019NM_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 submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -
Retinitis pigmentosa Pathogenic:4Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardApr 01, 2021The 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. -
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Pathogenic, criteria provided, single submitterresearchOphthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology BaselJul 24, 2023Clinical significance based on ACMG v2.0 -
Pathogenic, no assertion criteria providedresearchDepartment of Clinical Genetics, Copenhagen University Hospital, RigshospitaletApr 01, 2018- -
Usher syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 28, 2019The 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. -
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Pathogenic, reviewed by expert panelcurationClinGen Hearing Loss Variant Curation Expert PanelJul 28, 2019The 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 -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 26, 2019Variant 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. -
Retinal dystrophy Pathogenic:3
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJul 30, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyApr 15, 2021The 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). -
USH2A-Related Disorders Pathogenic:1Other:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016The 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. -
not provided, no classification providedphenotyping onlyGenomeConnect, 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 submitterclinical testingAmbry GeneticsMar 03, 2015- -
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyFaculty of Health Sciences, Beirut Arab UniversitySep 10, 2015- -
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinFeb 10, 2020ACMG classification criteria: PS4, PM3, PP1, PP3 -
USH2A-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 08, 2024The 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. -
Ear malformation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.48
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;T
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-9.4
D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MVP
0.98
MPC
0.27
ClinPred
0.88
D
GERP RS
5.8
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338902; hg19: chr1-216420460; COSMIC: COSV99048434; API