Submissions for variant NM_206933.4(USH2A):c.8284C>G (p.Pro2762Ala)

dbSNP: rs1188281491

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376219	SCV001573287	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.8284C>G 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: PS1, PM2, PM3. Based on this evidence we have classified this variant as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527328	SCV003524102	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2762 of the USH2A protein (p.Pro2762Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with USH2A-related conditions (PMID: 28041643, 29625443, 32037395, 32188678, 32675063, 33090715, 33124170). ClinVar contains an entry for this variant (Variation ID: 438028). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701571	SCV005203069	uncertain significance	not specified	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.8284C>G (p.Pro2762Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248630 control chromosomes (gnomAD). c.8284C>G has been reported in the literature in individuals affected with Inherited Retinal Disease/Retinitis Pigmentosa or Usher Syndrome (e.g. Chen_2014, Sun_2018, Zampagalione_2020, Gao_2021, Zhu_2021, Li_2022, Jin_2023). However, in many cases the phase of the variants found was not indicated, while some cases had a pathogenic/likely pathogenic variant (c.9958G>T/p.Gly3320Cys) in cis. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36110214, 32675063, 25133613, 29625443, 32188678, 32037395, 36464167). ClinVar contains an entry for this variant (Variation ID: 438028). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796212	SCV005416344	pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3_VeryStrong+PP4
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504749	SCV000598832	uncertain significance	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research