ClinVar Genomic variation as it relates to human health

The p.Leu1019fs variant in OTOGL has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1019 and l eads to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the OTOGL gene is an established disease mechanism in autosomal recessive heari ng loss. In summary, this variant meets criteria to be classified as pathogenic for nonsyndromic hearing loss in an autosomal recessive manner based on the pred icted impact of the variant.

This sequence change creates a premature translational stop signal (p.Leu1019Serfs*31) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 505260). For these reasons, this variant has been classified as Pathogenic.

Variant summary: OTOGL c.3081dupT (p.Leu1028SerfsX31) 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. The variant allele was found at a frequency of 7.5e-05 in 79880 control chromosomes. To our knowledge, no occurrence of c.3081dupT in individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 84B and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 505260). Based on the evidence outlined above, the variant was 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 deafness, autosomal recessive 84B (MIM#614944). (I) 0106 - This gene is associated with autosomal recessive disease. (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) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as pathogenic (ClinVar). (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) 1201 - Heterozygous variant detected in trans with a second pathogenic variant in a recessive disease. A deletion on 12q21.31 encompassing exons 10-42 of the OTOGL gene was identified on microarray (VCGS ID#23C107899). (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign