ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Gln347*) in the USH1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH1C are known to be pathogenic (PMID: 10973247, 17407589, 20301442, 21203349). This variant is present in population databases (rs762551629, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 500413). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 18A (MIM#602092) and Usher syndrome, type 1C (MIM#276904). Dominant negative is a suggested mechanism for rare autosomal dominant non-syndromic hearing loss (NSHL) (PMID: 31858762). (I) 0106 - This gene is associated with autosomal recessive disease. A single, large family with a heterozygous missense variant has been reported with autosomal dominant NSHL (PMID: 31858762). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic, and are generally observed in patients with Usher syndrome (OMIM, PMID: 27957503). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic (ClinVar), but also as a VUS due to insufficient information (deafnessvariationdatabase). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The USH1C c.1039C>T variant is predicted to result in premature protein termination (p.Gln347*). This variant has been reported with a second USH1C variant in an individual with Usher syndrome (Supplementary Table 3, Feenstra et al. 2022. PubMed ID: 36011334). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Nonsense variants in USH1C are expected to be pathogenic. This variant is interpreted as likely pathogenic.