Submissions for variant NM_206933.4(USH2A):c.1859G>T (p.Cys620Phe)

gnomAD frequency: 0.00002  dbSNP: rs758571672

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171545	SCV001334332	pathogenic	Usher syndrome	2023-10-24	reviewed by expert panel	curation	The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) in the European(non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID: 22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607*, p.Glu767Serfs*21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID: 36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023).
Counsyl	RCV000664581	SCV000788568	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-05-18	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761343	SCV000891329	likely pathogenic	Usher syndrome type 2A	2016-10-05	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000761343	SCV001156374	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208650	SCV001380051	pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 620 of the USH2A protein (p.Cys620Phe). This variant is present in population databases (rs758571672, gnomAD 0.004%). This missense change has been observed in individuals with Usher syndrome (PMID: 16963483, 22135276; Invitae). ClinVar contains an entry for this variant (Variation ID: 549981). 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%. Experimental studies have shown that this missense change affects USH2A function (PMID: 16114888). This variant disrupts the p.Cys620 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 24944099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001171545	SCV001652947	likely pathogenic	Usher syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Cys620Phe variant in USH2A has been reported in at least 2 individuals with Usher syndrome, including two compound heterozygotes (Le Quesne Stabej 2012). It has also been reported in ClinVar (Variation ID 549981). The p.Cys620Phe variant has been identified in 0.004% (5/129062) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant at the same position, p.Cys620Tyr has been reported in a homozygous individual with Usher syndrome (Baux 2014). In addition, an in vitro functional study suggests that this variant results in a failure of the Usherin peptide to co-immunoprecipitate fibronectin, which may indicate a disruption of normal protein function (Bhattacharya 2005); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PP4, PS3_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171545	SCV003934274	pathogenic	Usher syndrome	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.1859G>T (p.Cys620Phe) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) 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 1.6e-05 in 251316 control chromosomes (gnomAD). c.1859G>T has been reported in the literature in multiple individuals affected with Usher Syndrome (examples: Feenstra_2002, Stabej_2012, Molina-Ramirez_2020, Hagag_USH2A_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated this variant abolishes fibronectin/collagen interaction (example: Bhattacharya_2005). The following publications have been ascertained in the context of this evaluation (PMID: 22135276 , 32176120, 31266775, 33089500, 36011334, 16114888). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004533461	SCV004103841	likely pathogenic	USH2A-related disorder	2022-11-23	criteria provided, single submitter	clinical testing	The USH2A c.1859G>T variant is predicted to result in the amino acid substitution p.Cys620Phe. This variant has been reported as causative for Usher syndrome (Le Quesne Stabej et al. 2012. PubMed ID: 22135276; Molina-Ramírez et al. 2020. PubMed ID: 32176120). Functional studies have suggested that this variant does not affect collagen binding (Bhattacharya et al. 2004. PubMed ID: 14676276), but abolishes fibronectin binding (Bhattacharya and Cosgrove. 2005. PubMed ID: 16114888). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216462734-C-A). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003472065	SCV004200733	likely pathogenic	Retinitis pigmentosa 39	2024-03-10	criteria provided, single submitter	clinical testing