ClinVar

Description

Variant summary: USH2A c.5399G>A (p.Trp1800X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250992 control chromosomes (gnomAD). c.5399G>A has been reported in the literature in individuals affected with Usher Syndrome and Retinitis Pigmentosa (Baux_2014, Lenarduzzi_2015, Weisschuh_2020, Mansard_2021). Multiple patients were reported as compound heterozygous, carrying a second (likely) pathogenic variant, and at least one of which was confirmed in trans based on parental testing. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.