ClinVar

Description

Variant summary: USH2A c.12448A>G (p.Thr4150Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR0003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12448A>G has been reported in the literature in at-least three individuals, once as a solo allele in a family with Retinitis Pigmentosa (RP), second as a solo complex allele, c.[12448A>G;5012G>A] in a family with RP (Sharon_2020), and third as a compound heterozygous genotype (with c.1841-2A>G) in an individual with sporadic RP (Weisschuh_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic(n=2). At-least two of these submitters can be traced to an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.