Submissions for variant NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr)

gnomAD frequency: 0.00056  dbSNP: rs148660051

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000482080	SCV000231295	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000505000	SCV000245680	pathogenic	Retinitis pigmentosa	2021-03-29	criteria provided, single submitter	clinical testing	The p.Cys3358Tyr variant in USH2A has been reported in over 15 individuals with retinitis pigmentosa, with at least 9 of these individuals being compound heterozygous for a pathogenic variant on the remaining copy of USH2A (Calzetti 2018 PMID:29953849, Garcia-Garcia 2011 PMID:22004887, LeQuesne Stabej 2012 PMID:22135276, Lenassi 2015 PMID:25649381, McGee 2010 PMID:20507924, Neveling 2012 PMID:22334370, Stone 2018 PMID:28559085, van Huet 2015 PMID:25999674, Wang 2014 PMID:25097241, Zhao 2015 PMID:25472526, Avila-Fernandez 2010 PMID:21151602). Two of these individuals were reported to have features of atypical type 2 Usher syndrome, with a later onset hearing loss (Garcia-Garcia 2011 PMID:22004887, Lenassi 2015 PMID:25649381), and one was reported to have hearing loss though age of onset was not noted (Calzetti 2018 PMID:29953849). The variant has been identified in 98/128872 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa and/or atypical type 2 Usher syndrome, based on the previously reported individuals. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000190637	SCV000538073	likely pathogenic	Usher syndrome type 2A	2016-01-27	criteria provided, single submitter	clinical testing	The c.10073G>A (p.Cys3358Tyr) missense variant in the USH2A gene has been previously reported in several individuals affected with Usher Syndrome or Retinitis Pigmentosa. This allele was observed in 13 cases out of 914 affected alleles (Lenassi et al., 2015) and is significantly higher than the allele frequency in the ExAC database (13/121292). This variant is often seen in trans with other pathogenic variants (Garcia-Garcia et al., 2011; Le Quesne Stabej et al., 2012; Neveling et al., 2012; Lenassi et al., 2015). This c.10073G>A allele has been reported at low frequency, or is absent in other population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA). Multiple in silico algorithms predict this variant to have a deleterious effect GERP = 5.76; CADD = 22.4; PolyPhen = 1; SIFT = 0). Reputable diagnostic laboratories have reported this variant as either Likely Pathogenic or Pathogenic for either, Retinitis Pigmentosa or Usher Syndrome, Type 2A. Therefore, this collective evidence supports the classification of the c.10073G>A (p.Cys3358Tyr) as a recessive Likely Pathogenic variant for Usher syndrome, type IIA.
GeneDx	RCV000482080	SCV000565648	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	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: 28559085, 32531858, 34758253, 22334370, 25472526, 22004887, 20507924, 25649381, 22135276, 21151602, 25999674, 25097241, 26667666, 29953849, 31456290, 31980526, 32176120, 32581362, 31589614, 33576794, 33258288, 33737949, 32037395, 35266249)
Fulgent Genetics, Fulgent Genetics	RCV000515419	SCV000611246	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-02-10	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000179099	SCV000803576	likely pathogenic	Retinitis pigmentosa 39	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Retinitis pigmentosa 39, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Strong => PM3 upgraded in strength to Strong (PMID:22334370) (PMID:25649381).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482080	SCV000952339	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3358 of the USH2A protein (p.Cys3358Tyr). This variant is present in population databases (rs148660051, gnomAD 0.07%). This missense change has been observed in individual(s) with Usher syndrome or retinal disease (PMID: 22004887, 22135276, 25472526, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197932). 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.
Myriad Genetics, Inc.	RCV000190637	SCV001193786	likely pathogenic	Usher syndrome type 2A	2019-12-17	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.10073G>A(C3358Y) is classified as likely pathogenic in the context of USH2A-related disorders and is primarily associated with retinitis pigmentosa. Sources cited for classification include the following: PMID 22004887, 22334370, 26667666, 25472526, 25097241, 25649381 and 20507924. Classification of NM_206933.2(USH2A):c.10073G>A(C3358Y) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics	RCV001073681	SCV001239234	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000482080	SCV001246252	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174974	SCV001338457	pathogenic	Usher syndrome	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.10073G>A (p.Cys3358Tyr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251094 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00035 vs 0.011), allowing no conclusion about variant significance. c.10073G>A has been reported in the literature in multiple individuals affected with Usher Syndrome/Retinitis Pigmentosa/Inherited Retinal Diseases (IRD) (example, Garcia-Garcia_2011, LeQuesneStabej_2012, Lenassi_2015, Neveling_2012, Wang_2014, Calzetti_2018, McGee_2010, Weisschuh_2020). 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000190637	SCV001520105	likely pathogenic	Usher syndrome type 2A	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 25097241, 20507924, 25472526, 22004887, ClinVar ID: 197932]
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000179099	SCV001573662	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.10073G>A 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: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505000	SCV001950390	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Cys3358Tyr 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: PS1, PM2, PM3, 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.
Revvity Omics, Revvity	RCV000482080	SCV002021605	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000179099	SCV002556913	pathogenic	Retinitis pigmentosa 39	2021-09-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000190637	SCV002557348	pathogenic	Usher syndrome type 2A	2022-02-02	criteria provided, single submitter	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 (MIM# 6138093). (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 tyrosine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 111 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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with both Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (MIM# 6138093), and classified as both like pathogenic and pathogenic by diagnostic laboratories in Clinvar (PMID: 22004887, 25649381). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000505000	SCV004030329	pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Genome-Nilou Lab	RCV000179099	SCV004182598	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000190637	SCV004182599	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000179099	SCV004207688	pathogenic	Retinitis pigmentosa 39	2024-03-29	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000190637	SCV000536900	likely pathogenic	Usher syndrome type 2A	2016-07-19	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505000	SCV000598759	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000179099	SCV000678128	likely pathogenic	Retinitis pigmentosa 39	2016-12-16	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000505000	SCV001161345	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000179099	SCV001760012	pathogenic	Retinitis pigmentosa 39		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000190637	SCV002011779	likely pathogenic	Usher syndrome type 2A	2021-08-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537478	SCV004112532	pathogenic	USH2A-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The USH2A c.10073G>A variant is predicted to result in the amino acid substitution p.Cys3358Tyr. This variant has been reported along with a second pathogenic variant in many individuals with autosomal recessive nonsyndromic retinitis pigmentosa or Usher syndrome (Calzetti et al. 2018. PubMed ID: 29953849; Table S4, Colombo et al. 2021. PubMed ID: 33576794; Lynn et al. 2023. PubMed ID: 36672815; Molina-Ramírez et al. 2020. PubMed ID: 32176120; Table S4, Panneman et al. 2023. PubMed ID: 36819107), although it has been associated primarily with nonsyndromic retinal degeneration in patients without early onset hearing loss (Leanassi et al. 2015. PubMed ID: 25649381). This variant is reported in 0.076% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.