Submissions for variant NM_206933.4(USH2A):c.1556A>G (p.Gln519Arg)

gnomAD frequency: 0.00007  dbSNP: rs199672621

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041792	SCV000065488	uncertain significance	not specified	2010-08-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Gln519Arg varia nt in USH2A has not been reported in the literature but was identified in our la boratory in one indivudal with another clear etiology for hearing loss. This res idue is conserved in mammals; however, computational analyses (PolyPhen, SIFT, A lignGVGD) provide inconsistent predictions regarding the impact to the protein. It should be noted that this lab has only sequenced the USH2A gene in XXX indivi duals such that the full spectrum of benign variation has not yet been defined f or this gene, increasing the possibility that this may be a benign variant. In s ummary, the clinical significance of this variant cannot be determined with cert ainty at this time; however, based upon the arguments described above, we would lean towards a more likely benign role.
CeGaT Center for Human Genetics Tuebingen	RCV000488160	SCV000574829	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000665727	SCV000789893	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-03-22	criteria provided, single submitter	clinical testing
Invitae	RCV000488160	SCV003305357	uncertain significance	not provided	2022-03-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 519 of the USH2A protein (p.Gln519Arg). This variant is present in population databases (rs199672621, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48469). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV003450823	SCV004182858	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001831701	SCV004182859	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831701	SCV002093982	uncertain significance	Usher syndrome type 2A	2020-04-06	no assertion criteria provided	clinical testing