Description
Variant summary: SLC26A4 c.147C>G (p.Ser49Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 141150 control chromosomes, predominantly at a frequency of 0.0038 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0038 vs 0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.147C>G has been reported in the literature in heterozygous individuals affected with non-syndromic hearing loss, congenital hypothyroidism, and Pendred Syndrome (e.g. Du_2014, Zhao_2014, Ideura_2019, Zhang_2022), however without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. Functional studies have found the variant has little to no effect on protein expression, membrane localization, and ion transport activity when compared with the wild-type protein (e.g. Wasano_2020, Zhang_2022). Five ClinVar submitters including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
