The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold ≤0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID: 19204907, 31599023). This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID: 19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID: 9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID: 14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023).