Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000151586 | SCV000199738 | uncertain significance | not specified | 2014-11-08 | criteria provided, single submitter | clinical testing | The p.Pro627Arg variant in OTOA has not been previously reported in individuals with hearing loss or in large population studies. Another variant at this positi on (p.Pro627Ser) has been reported in 2 Pakistani individuals with non-syndromic hearing loss, and segregated with disease in 2 affected siblings from 2 familie s (Lee 2013), suggesting that changes that this position may affect the protein. Computational prediction tools and conservation analyses suggest that the p.Pro 627Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located at the last nucleotide of the exon, which is part of the 5' splice region. Computation al tools do not suggest an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the p.Pro627Arg variant is uncertain. |
| Labcorp Genetics |
RCV001850067 | SCV002272559 | likely pathogenic | not provided | 2023-04-16 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 627 of the OTOA protein (p.Pro627Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive deafness (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 164825). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Pro627 amino acid residue in OTOA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23173898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |