ClinVar

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.1841-2 A>G variant in USH2A gene has benn found in 4/113596 alleles only in european non-finnish population (0.0012% with 95% CI) meeting PM2 rule . This type of variant is predicted to generate a lost of the acceptor splicing site in USH2A gene , which is a known mechanism of disease, PVS1. The c.1841-2 A>G has been identified in trans with different pathogenic variants in at least 10 individuals (PM3_VS): 2 patients with retinitis pigmentosa, 9 cases of type 2 Usher patients (PP4), one type 3 Usher patient and 3 hearing loss patients (variants detected in early childhood); (PMID:12525556, 18641288, 19683999, 21738395, 22004887, 22135276, 24875298, 24944099, 25558175, 25575603, 29986705, 27460420, this report). The c.1841-2 A>G segregated correctly in two familial cases: one family composed of two siblings with retinitis pigmentosa and two unaffected siblings and a second familiy case composed of two siblings with hearing loss (PMID: 12525556, 24875298) applying to PP1_Mod. Functional studies in COS-7 cells using minigen system demonstrated that this variant generated the skippining of exon 11 leading to a freamshift: p.Gly614Aspfs6* (PMID20497194); PS3_Supp.Considering PM2, PVS1_VS, PP4, PP1_M, PS3_S the variant is classfied as Pathogenic for Usher Syndrome and retinitis pigmentosa.