Submissions for variant NM_206933.4(USH2A):c.4645C>T (p.Arg1549Ter)

gnomAD frequency: 0.00002  dbSNP: rs199679165

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000605510	SCV000710864	pathogenic	Rare genetic deafness	2017-08-15	criteria provided, single submitter	clinical testing	The p.Arg1549X variant in USH2A has been previously reported in over 10 individu als with Usher syndrome, most of whom were homozygous or compound heterozygous w ith a second pathogenic USH2A variant (Baux 2007, Bonnet 2016, Garcia-Garcia 201 1, Le Quesne Stabej 2012, Maranhao 2015, McGee 2010, Sandberg 2008, Zhao 2015). This variant has been identified in 2/111610 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs199679 165). Although this variant has been seen in the general population, its frequen cy is low enough to be consistent with a carrier frequency for autosomal recessi ve Usher syndrome. This nonsense variant leads to a premature termination codon at position 1549, which is predicted to lead to a truncated or absent protein. L oss of function of the USH2A gene is an established disease mechanism in autosom al recessive Usher syndrome. In summary, this variant meets criteria to be clas sified as pathogenic for autosomal recessive Usher syndrome, based on the previo usly reported individuals with Usher syndrome, a low frequency in the general po pulation, and predicted impact to the protein.
Counsyl	RCV000669125	SCV000793839	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-09-11	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002689	SCV001156369	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208453	SCV001379842	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1549*) 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 (rs199679165, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 26352687, 28559085, 29899460). ClinVar contains an entry for this variant (Variation ID: 504513). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001002689	SCV002767083	pathogenic	Usher syndrome type 2A	2020-05-01	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 22 of 72). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. More than 10 NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in unrelated patients with Usher syndrome and retinitis pigmentosa (PMIDs: 17405132, 26352687, 29899460), and as pathogenic in ClinVar. (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Genome-Nilou Lab	RCV003451354	SCV004182216	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001002689	SCV004182217	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003451354	SCV004207700	pathogenic	Retinitis pigmentosa 39	2024-03-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001002689	SCV001462264	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001002689	SCV001760018	pathogenic	Usher syndrome type 2A		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732969	SCV005351106	pathogenic	USH2A-related disorder	2024-07-31	no assertion criteria provided	clinical testing	The USH2A c.4645C>T variant is predicted to result in premature protein termination (p.Arg1549*). This variant has been reported many times in individuals with Usher syndrome or early onset retinal degeneration (see for examples: Baux et al. 2007. PubMed ID: 17405132; Maranhao et al. 2015. PubMed ID: 26352687; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Garcia-Garcia et al. 2011. PubMed ID: 22004887). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in USH2A are an established mechanism of disease. This variant is interpreted as pathogenic.