The p.Cys282Tyr variant in SLC26A4 is present in 0.0053% of European (non-Finnish) chromosomes by gnomAD v2.1.1, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss expert Panel for autosomal recessive hearing loss (PM2). The REVEL computational prediction analysis tool produced a score of 0.719, which is above the threshold necessary to apply PP3. This variant has been detected in 3 probands with hearing loss. For all of the patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:26969326, Partners LMM unpublished data SCV000060163.6, EGL Genetic Diagnostics unpublished data SCV000343642.4). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, PMID:26969326). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP3, PP4, PS3_Supporting).