ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (27 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been reported as a VUS in ClinVar and in an adult patient with early onset myopia where a second variant in the same gene was also identified, however, pathogenicity of the variant could not be confirmed (PMID: 26747767 ). It has also been reported in the heterozygous state in a family with severe hearing loss and in another family where an alternative diagnosis was identified (PMID: 25388789; 32767731) (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign