Submissions for variant NM_206933.4(USH2A):c.9958G>T (p.Gly3320Cys)

dbSNP: rs1285853856

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376218	SCV001573286	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.9958G>T 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	RCV001376751	SCV001573912	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 3320 of the USH2A protein (p.Gly3320Cys). This variant also falls at the last nucleotide of exon 50, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa and Usher syndrome (PMID: 26338283, 29625443, 31960602, 32188678, 32675063). 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: 438037). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 36362125). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001376218	SCV004182628	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376218	SCV004208136	likely pathogenic	Retinitis pigmentosa 39	2024-01-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701572	SCV005202485	pathogenic	Usher syndrome	2024-07-12	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9958G>T (p.Gly3320Cys) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site and three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in partial or whole exon 50 skipping (Reurink_2022). The variant was absent in 251248 control chromosomes. c.9958G>T has been reported in the literature as homozygous or compound heterozygous genotype in individuals affected with clinical features of Usher Syndrome (Chen_2014, Sun_2018, Dan_2020, Liu_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25133613, 31960602, 33090715, 36362125, 29625443). ClinVar contains an entry for this variant (Variation ID: 438037). Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504889	SCV000598847	uncertain significance	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001834625	SCV002088375	likely pathogenic	Usher syndrome type 2A	2021-09-14	no assertion criteria provided	clinical testing