Submissions for variant NM_206933.4(USH2A):c.15281C>T (p.Pro5094Leu)

gnomAD frequency: 0.00004  dbSNP: rs727503714

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152563	SCV000201800	uncertain significance	not specified	2014-06-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro5094Leu vari ant in USH2A has not been previously reported in individuals with hearing loss a nd was absent from large population studies. The proline (Pro) at position 5094 is not conserved in mammals or evolutionary distant species, suggesting that var iation at this position may be tolerated. Other computational prediction tools d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of this variant cannot be determined with certainty; however, based upon conservation data, we would lean towards a more likely beni gn role.
Counsyl	RCV000666221	SCV000790478	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-04-04	criteria provided, single submitter	clinical testing
Invitae	RCV001239388	SCV001412261	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5094 of the USH2A protein (p.Pro5094Leu). This variant is present in population databases (rs727503714, gnomAD 0.01%). 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: 166415). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A 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.
Fulgent Genetics, Fulgent Genetics	RCV000666221	SCV002780674	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001239388	SCV003921455	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Reported without a second variant in a patient with family history of hearing loss in published literature (Almontashiri et al., 2018); additional information is limited; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29048421)
Genome-Nilou Lab	RCV003453115	SCV004181592	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001826813	SCV004181603	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826813	SCV002088192	uncertain significance	Usher syndrome type 2A	2020-01-16	no assertion criteria provided	clinical testing