ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 12q23.1
  • GRCh37/hg19 chr12: 100,750,857-100,815,837
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr12: 100,357,074-100,422,055
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000012.11) (NC_000012.12)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
26797701 Ryu et al. 2016 identified the c.616dupA (p.Met206AsnfsX4) variant in a Korean proband with autosomal dominant sensorineural hearing loss (ADSNHL). The hearing loss was bilateral and severe and the patient was determined to be negative for TJP2, CLDN14 EYA4, GRHL2 mutations, though the SLC17A8 was the only other gene sequenced. The proband was the only family member sequenced but the family history was clearly AD (7 other affecteds).
28647561 Ryu et al. 2017 identified a family with 3 affected and 1 unaffected family members who underwent whole exome sequencing. They found that 72 non-synonymous variants cosegregated with disease but concluded that the c.763+1G>T variant in SLC17A8 was the cause of the progressive high frequency hearing loss in this Korean family. Though no information was provided about the other 71 variants that segregated with hearing loss, a minigene assay revealed that the variant caused an in frame skipping of exon 6 which is 65AA/292AA (22%) of the protein according to NM_001145308.4. Therefore this is consistent with a loss of function (LOF) variant that may be causing disease through haploinsufficiency

Haploinsufficiency phenotype comments:

There have been two convincing loss of function variants reported in the literature that show that haploinsufficiency may be the mechanism of SLC17A8-related nonsyndromic hearing loss. Of note, the hearing loss phenotype may not be perfectly consistent as one family was reported to have progressive, high frequency hearing loss, while the other family was reported to have bilateral severe hearing loss. The progressive hearing loss phenotype was also seen in another family (unpublished Iowa Family 1490) who had a p.Ala211V variant that was functionally shown by Ramet et al. 2017 28314816 to reduce expression of the protein in synaptic terminals by 70% but does not alter protein function. Additionally, Akil et al. 2012, 22841313 found that restoration of the SLC17A8 product, VGLUT3 after a knockout (KO) using viral mediated gene therapy was successful in recovering hearing ability. The technique was found to be more effective and long lasting when performed earlier in life. They did note that no signs of spiral ganglion cell recovery were seen. This experiment provides convincing evidence of a homozygous loss of function causing progressive hearing loss, but does not show that haploinsufficiency is the mechanism for disease in humans. There are multiple experimental studies showing that VGLUT3 is essential for hearing loss in mice but it appears none used a heterozygous mouse. In summary, there are two convincing heterozygous LOF cases in humans and one missense functionally shown to cause reduced levels of the protein product that may cause a progressive hearing loss phenotype or a severe hearing loss phenotype. There is also experimental evidence showing that SLC17A8 is essential for hearing in mice, but only homozygous KO's have been studied. Variation in SLC17A8 has been reported in individuals with ADNSHL; furthermore, the overall evidence that SLC17A8, when altered, causes ADNSHL was expert reviewed by the ClinGen Hearing Loss Working Group and classified as STRONG.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There is no evidence in the literature to support a triplosensitivity mechanism of disease for SLC17A8