Submissions for variant NM_206933.4(USH2A):c.949C>A (p.Arg317=)

gnomAD frequency: 0.00003  dbSNP: rs111033272

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824799	SCV000065652	pathogenic	Rare genetic deafness	2012-11-19	criteria provided, single submitter	clinical testing	The p.Arg317Arg (NM_206933.2 c.949C>A) variant in USH2A has been reported in 9 i ndividuals with Usher syndrome (Pennings 2004, Seyedahmadi 2004, Cremers 2007, D reyer 2008, Vache 2010, Bonnet 2011). A second variant in USH2A was found in tr ans in at least 3 of these individuals (Pennings 2004, Vache 2010, Bonnet 2011). This variant has also been reported in ClinVar (Variation ID#2358) as pathogeni c. mRNA studies show that this variant leads to abnormal splicing and a frameshi ft (Vache 2010). This variant has been identified in (8/126206) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs111033272). Although this variant has been seen in the general pop ulation, its frequency is low enough to be consistent with a recessive carrier f requency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon functional evide nce and its occurrence in individuals with this disease. ACMG/AMP Criteria appli ed: PVS1, PM2, PM3, PP5.
Eurofins Ntd Llc (ga)	RCV000412796	SCV000339779	pathogenic	not provided	2016-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000412796	SCV000490867	pathogenic	not provided	2020-02-05	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function (Vache et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27957503, 15043528, 15015129, 30904819, 20513143, 26927203, 24944099, 23891399, 28944237, 15241801, 15325563, 21569298, 18273898, 16963483, 25575603, 30609409)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627017	SCV000747720	pathogenic	Blindness; Rod-cone dystrophy; Pigmentary retinopathy; Abnormal macular morphology; Retinal pigment epithelial atrophy	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763297	SCV000893962	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199595	SCV001162766	pathogenic	Usher syndrome type 2	2020-01-09	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412796	SCV001219336	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 317 of the USH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033272, gnomAD 0.006%). This variant has been observed in individual(s) with Usher syndrome type IIa or nonsydromic retinitis pigmentosa (PMID: 15241801, 20513143, 21569298, 26927203). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2358). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20513143). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075725	SCV001241353	pathogenic	Retinal dystrophy	2019-05-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000412796	SCV001248865	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000002452	SCV001369018	pathogenic	Usher syndrome type 2A	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000412796	SCV001448877	pathogenic	not provided	2017-09-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000984234	SCV004182925	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002452	SCV004182926	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984234	SCV004208204	pathogenic	Retinitis pigmentosa 39	2024-03-08	criteria provided, single submitter	clinical testing
OMIM	RCV000002452	SCV000022610	pathogenic	Usher syndrome type 2A	2004-04-01	no assertion criteria provided	literature only
Counsyl	RCV000002452	SCV001132312	likely pathogenic	Usher syndrome type 2A	2019-01-24	no assertion criteria provided	clinical testing
Counsyl	RCV000984234	SCV001132313	likely pathogenic	Retinitis pigmentosa 39	2019-01-24	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000412796	SCV001922732	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412796	SCV001959112	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002452	SCV002094005	pathogenic	Usher syndrome type 2A	2021-01-29	no assertion criteria provided	clinical testing