Submissions for variant NM_206933.4(USH2A):c.1256G>T (p.Cys419Phe)

gnomAD frequency: 0.00008  dbSNP: rs121912600

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824795	SCV000065420	pathogenic	Rare genetic deafness	2010-10-28	criteria provided, single submitter	clinical testing	The Cys419Phe variant in USH2A has been reported in 16/246 probands with Usher s yndrome Type 2 and was absent from 380 control chromosomes (p<0.0001, Weston 200 0, Pennings 2004, Seyedahmadi 2004). Many of these probands were homozygous or c ompound heterozygous. In addition, this variant is thought to be a founder mutat ion in the Dutch population (Pennings 2004). In summary, this variant meets our criteria to be classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000224697	SCV000232370	pathogenic	not provided	2016-04-21	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224697	SCV000281626	pathogenic	not provided	2016-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000224697	SCV000583303	pathogenic	not provided	2024-05-24	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: 24944099, 22334370, 33576794, 32853555, 34758253, 24265693, 10729113, 15043528, 22135276, 28559085, 31980526, 32176120, 33360097, 32037395, 36011334, 36284670, 34781295, 35266249, 28761320, 36819107, 20301515, 37237007, 25999674, 28041643, 18641288, 24498627, 16963483, 15015129, 15325563, 37108761, 25649381)
Illumina Laboratory Services, Illumina	RCV000778222	SCV000914388	pathogenic	USH2A-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the USH2A c.1256G>T (p.Cys419Phe) missense variant has been identified in a homozygous state in two patients with Usher syndrome, in a compound heterozygous state in 13 patients of whom ten were diagnosed with Usher syndrome and three with retinitis pigmentosa (RP), and in a heterozygous state in 16 patients of whom ten were diagnosed with Usher syndrome and six with RP (Weston et al. 2000; Van Wijk et al. 2004; Seyedahmadi et al. 2004; Sandberg et al. 2008; Neveling et al. 2012; Le Quesne Stabe et al. 2012; Eisenberger et al. 2013; Besnard et al. 2014; Cremers et al. 2014; Pennings et al. 2004; Van Huet et al. 2015). The p.Cys419Phe variant is a possible Dutch founder variant as deduced by haplotype analysis by Pennings et al. (2004). The p.Cys419Phe variant was absent in at least 1000 controls and is reported at a frequency of 0.000093 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Cys419Phe variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224697	SCV001223238	pathogenic	not provided	2024-01-19	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 419 of the USH2A protein (p.Cys419Phe). This variant is present in population databases (rs121912600, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10729113, 15043528, 15241801, 22334370, 24265693, 24498627, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Dutch ancestry (PMID: 15241801). ClinVar contains an entry for this variant (Variation ID: 2359). 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.
Blueprint Genetics	RCV001074823	SCV001240423	pathogenic	Retinal dystrophy	2019-07-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224697	SCV001248863	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000778222	SCV001251480	pathogenic	USH2A-related disorder		criteria provided, single submitter	research	USH2A c.1256G>T (p.C419F) has been described as a pathogenic variant and has been reported in the homozygous or compound heterozygous state in multiple individuals with Usher syndrome type IIA and nonsyndromic retinitis pigmentosa (PMID: 15015129; 15241801;15325563; 10729113; 22135276; 24944099; 25999674).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504809	SCV001362170	pathogenic	Usher syndrome	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.1256G>T (p.Cys419Phe) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) 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 4e-05 in 250184 control chromosomes. c.1256G>T has been reported in the literature in multiple individuals affected with Usher syndrome and/or Retinitis Pigmentosa (example, Weston_2000, Neveling_2012, Eisenberger_2013, Stone_2017). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000984315	SCV001573447	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.1256G>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: PS4, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482817	SCV002780180	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-08-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000984315	SCV004182892	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002453	SCV004182893	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984315	SCV004207721	pathogenic	Retinitis pigmentosa 39	2024-03-01	criteria provided, single submitter	clinical testing
OMIM	RCV000002453	SCV000022611	pathogenic	Usher syndrome type 2A	2004-04-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504809	SCV000598775	uncertain significance	Usher syndrome	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000002453	SCV000804732	pathogenic	Usher syndrome type 2A	2016-09-01	no assertion criteria provided	clinical testing
Counsyl	RCV000002453	SCV001132499	pathogenic	Usher syndrome type 2A	2017-02-08	no assertion criteria provided	clinical testing
Counsyl	RCV000984315	SCV001132500	pathogenic	Retinitis pigmentosa 39	2017-02-08	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002453	SCV001457324	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000002453	SCV001760023	pathogenic	Usher syndrome type 2A		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000224697	SCV001921479	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224697	SCV001958308	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224697	SCV001968070	pathogenic	not provided		no assertion criteria provided	clinical testing