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
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| USH2A | ENST00000307340.8 | c.2276G>T | p.Cys759Phe | missense_variant | Exon 13 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
| USH2A | ENST00000366942.3 | c.2276G>T | p.Cys759Phe | missense_variant | Exon 13 of 21 | 1 | ENSP00000355909.3 | |||
| USH2A | ENST00000674083.1 | c.2276G>T | p.Cys759Phe | missense_variant | Exon 13 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes 0.00131 AC: 199AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000969 AC: 243AN: 250722Hom.: 0 AF XY: 0.000893 AC XY: 121AN XY: 135474
GnomAD4 exome AF: 0.00148 AC: 2158AN: 1461782Hom.: 5 Cov.: 31 AF XY: 0.00142 AC XY: 1029AN XY: 727202
GnomAD4 genome 0.00131 AC: 199AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102AN XY: 74418
ClinVar
Submissions by phenotype
not provided Pathogenic:11
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. -
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USH2A: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
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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. -
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) -
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Retinitis pigmentosa 39 Pathogenic:9
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This variant was identified as compound heterozygous with NM_206933.4:c.12698G>A._x000D_ Criteria applied: PS4, PM3_STR, PP1, PP3 -
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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. -
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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. -
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PS1, PS4, PP3, PP4, PM3 -
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Usher syndrome type 2A Pathogenic:9
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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. -
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Criteria applied: PM3_VSTR,PP1_STR,PP3 -
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 -
Retinitis pigmentosa Pathogenic:4Other:1
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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. -
Clinical significance based on ACMG v2.0 -
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Usher syndrome Pathogenic:4
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. -
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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 -
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. -
Retinal dystrophy Pathogenic:4
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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). -
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USH2A-related disorder Pathogenic:2Other:1
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. -
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. -
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. -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1Other:1
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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. -
Inborn genetic diseases Pathogenic:1
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Autosomal recessive retinitis pigmentosa Pathogenic:1
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See cases Pathogenic:1
ACMG classification criteria: PS4, PM3, PP1, PP3 -
Ear malformation Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at