Submissions for variant NM_206933.4(USH2A):c.6602A>T (p.Gln2201Leu)

gnomAD frequency: 0.00004  dbSNP: rs143107117

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725071	SCV000333774	uncertain significance	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000334652	SCV000711238	uncertain significance	not specified	2017-09-22	criteria provided, single submitter	clinical testing	The p.Gln2201Leu variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 7/111432 of Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org/; dbSNP rs143107117). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. Computational prediction tools and conservation analysis suggest that the p .Gln2201Leu variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Gln2201Leu variant is uncertain.
GeneDx	RCV000725071	SCV002015792	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000725071	SCV003514649	uncertain significance	not provided	2022-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2201 of the USH2A protein (p.Gln2201Leu). This variant is present in population databases (rs143107117, gnomAD 0.006%). 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: 282354). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV003454788	SCV004181642	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001835748	SCV004181643	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835748	SCV002090881	uncertain significance	Usher syndrome type 2A	2020-08-10	no assertion criteria provided	clinical testing