Submissions for variant NM_206933.4(USH2A):c.8740C>T (p.Arg2914Ter)

gnomAD frequency: 0.00003  dbSNP: rs766590491

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213731	SCV000271475	pathogenic	Rare genetic deafness	2015-04-24	criteria provided, single submitter	clinical testing	The p.Arg2914X variant in USH2A has been previously reported in 4 individuals wi th Usher syndrome (Baux 2014, McGee 2010) and 1 individual with retinitis pigmen tosa (RP) (Zhao 2015), however hearing loss was not evaluated in the latter. At least 4 of these individuals were compound heterozygous for a second pathogenic variant in USH2A. This variant has been identified in 1/66678 European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org), though this frequency is low enough to be consistent with a recessive carrier fr equency. This nonsense variant leads to a premature termination codon at positio n 2914, which is predicted to lead to a truncated or absent protein. Loss of fun ction of the USH2A gene is an established disease mechanism in Usher syndrome. I n summary, the p.Arg2914X variant in USH2A meets our criteria to be classified a s pathogenic for autosomal recessive Usher syndrome based upon the predicted imp act to the protein and the previously reported individuals with Usher syndrome ( www.partners.org/personalizedmedicine/lmm).
Blueprint Genetics	RCV001075409	SCV001241031	pathogenic	Retinal dystrophy	2018-07-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091129	SCV001246994	pathogenic	not provided	2017-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001091129	SCV001399316	pathogenic	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2914*) 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 (rs766590491, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with USH2A-related conditions (PMID: 24944099, 25472526). ClinVar contains an entry for this variant (Variation ID: 228417). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001091129	SCV001447805	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000666615	SCV001573696	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.8740C>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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.
Genome-Nilou Lab	RCV000666615	SCV004182778	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001273711	SCV004182779	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666615	SCV004206330	pathogenic	Retinitis pigmentosa 39	2024-03-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000666615	SCV000790935	pathogenic	Retinitis pigmentosa 39	2017-04-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001273711	SCV001457081	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing