Submissions for variant NM_206933.4(USH2A):c.1227G>A (p.Trp409Ter)

gnomAD frequency: 0.00002  dbSNP: rs397517979

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438959	SCV000515864	pathogenic	not provided	2015-03-18	criteria provided, single submitter	clinical testing	The W409X nonsense variant in the USH2A gene has been reported previously in association withUsher syndrome type II and isolated retinitis pigmentosa (Weston et al., 2000; Neveling et al., 2012). Thisvariant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W409X variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. We interpret the W409X variant as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000589870	SCV000693909	pathogenic	Retinitis pigmentosa 39	2017-06-25	criteria provided, single submitter	research	Very rare in reference population databases, in gnomAD, 2/275918 chromosomes (PM2). Nonsense variant in known disease gene where loss of function results in disease (PVS1). Found in trans with previously reported likely pathogenic missense variant (p.Arg2894Lys) (PM3). Previously reported in three cases, two apparently unrelated Dutch families, one homozygous and the other a compound heterozygote with c.1256G>T (p.C419F) (in PMID:10729113) and compound heterozygous with c.12575G>A (p.R4192H) (PMID: 22334370).
Counsyl	RCV000667167	SCV000791574	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-05-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000438959	SCV001203571	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp409*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with USH2A-related conditions (PMID: 10729113, 22334370). ClinVar contains an entry for this variant (Variation ID: 379205). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000589870	SCV002556875	pathogenic	Retinitis pigmentosa 39	2021-02-03	criteria provided, single submitter	clinical testing	The USH2A c.1227G>A variant is classified as Pathogenic (PVS1, PM2, PM3)
Genome-Nilou Lab	RCV000589870	SCV004182898	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001833524	SCV004182899	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000589870	SCV004208402	pathogenic	Retinitis pigmentosa 39	2024-01-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816656	SCV005072098	pathogenic	Retinal dystrophy	2012-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000438959	SCV001925307	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000438959	SCV001959894	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000438959	SCV001976016	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001833524	SCV002093994	pathogenic	Usher syndrome type 2A	2021-06-10	no assertion criteria provided	clinical testing