rs80338902

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. BS1PS4PM3_StrongPP1_StrongPP4PP3

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

Scores

14
3
2

Clinical Significance

Pathogenic reviewed by expert panel P:48O: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 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 rank MANE Protein UniProt
USH2ANM_206933.4 linkc.2276G>T p.Cys759Phe missense_variant Exon 13 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.2276G>T p.Cys759Phe missense_variant Exon 13 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.2276G>T p.Cys759Phe missense_variant Exon 13 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.2276G>T p.Cys759Phe missense_variant Exon 13 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.2276G>T p.Cys759Phe missense_variant Exon 13 of 73 ENSP00000501296.1 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:48Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:11
-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

USH2A: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Sep 04, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 05, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 09, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Oct 31, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 20, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed in the homozygous state in a few unaffected individuals as well as in affected individuals who had different genetic etiologies for the phenotype, indicating reduced penetrance of this variant (PMID: 25823529, 12525556, 25097241); 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, 37644014, 36011402, 31964843, 36460718, 35052694, 36819107, 36909829, 36785559, 35248879, 37217489, 33749171, 37734845, 34906470, 32037395, 35836572, 34948090, 36051698, 36003347, 36034145, 36140798, 36011334, 34599368, 34781295, 35266249, 31877679, 35672333, 29912909, 25823529) -

Retinitis pigmentosa 39 Pathogenic:9
Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2013
UCLA Clinical Genomics Center, UCLA
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 16, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_206933.4:c.12698G>A._x000D_ Criteria applied: PS4, PM3_STR, PP1, PP3 -

Jul 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jul 12, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS1, PS4, PP3, PP4, PM3 -

Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jan 24, 2024
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.041%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32367058). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32367058). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000929258 /PMID: 32367058 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 01, 2016
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 03, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A Pathogenic:9
Feb 23, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 20, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 17, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

May 18, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 07, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PP1_STR,PP3 -

Retinitis pigmentosa Pathogenic:4Other:1
Apr 01, 2021
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jul 24, 2023
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Clinical significance based on ACMG v2.0 -

Apr 01, 2018
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Usher syndrome Pathogenic:4
Nov 26, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Aug 28, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jul 28, 2019
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: 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 w -

Retinal dystrophy Pathogenic:4
Jul 30, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Apr 15, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

USH2A-related disorder Pathogenic:2Other:1
Aug 21, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

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GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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. -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1Other:1
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GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: 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. -

Jan 31, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Inborn genetic diseases Pathogenic:1
Mar 03, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Autosomal recessive retinitis pigmentosa Pathogenic:1
Sep 10, 2015
Faculty of Health Sciences, Beirut Arab University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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See cases Pathogenic:1
Feb 10, 2020
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS4, PM3, PP1, PP3 -

Ear malformation Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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
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