Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000601975 | SCV000713494 | likely pathogenic | Rare genetic deafness | 2017-09-03 | criteria provided, single submitter | clinical testing | The p.Glu227X variant in SERPINB6 has not been previously reported in individual s with hearing loss, but has been identified in 1/17248 East Asian chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). A lthough this variant has been seen in the general population, its frequency is l ow enough to be consistent with a recessive carrier frequency. This nonsense var iant leads to a premature termination codon at position 227, which is predicted to lead to a truncated or absent protein. There is moderate evidence suggesting that truncating variants in SERPINB6 result in autosomal recessive hearing loss. One report describes a consanguineous family that were homozygous for a nonsens e variant (p.Glu245X) which segregated with hearing loss in four affected family members, and SERPINB6 protein expression was absent in leukocytes of homozygote s (Sirmaci 2010). Another study reported a proband with hearing loss who was com pound heterozygous for a frameshift and a canonical splice site variant (Kim 201 5). In addition, the SERPINB6 protein was also shown to be expressed in the mous e inner ear (Sirmaci 2010), and a knockout mouse model was shown to display hear ing loss and progressive cellular degeneration in the cochlea (Tan 2013). In sum mary, although additional evidence is needed to further support the gene-disease association, the p.Gly227X variant in SERPINB6 is likely pathogenic for autosom al recessive hearing loss. |