Submissions for variant NM_000441.2(SLC26A4):c.*239C>T

gnomAD frequency: 0.00237  dbSNP: rs113516368

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000314500	SCV000466115	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000353085	SCV000466116	uncertain significance	Pendred syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
King Laboratory, University of Washington	RCV000314500	SCV003844124	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-02-28	criteria provided, single submitter	research	This variant was found in compound heterozygosity with an SLC26A4 splicing variant that is known to be pathogenic/likely pathogenic, in two siblings with bilateral sensorineural hearing loss of onset <18 years and bilateral enlarged vestibular aqueduct (EVA), in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). These siblings’ family has no other history of hearing loss. This variant was found in cis orientation with SLC26A4 c.*200A>T. Both variants are located in the 3’ UTR of SLC26A4 and are predicted to affect miRNA binding sites. As of January 2023, both variants have been reported previously in an individual with Pendred syndrome and are currently classified as variants of unknown significance on ClinVar, and they are found in 103 heterozygous individuals on gnomAD. Based on compound heterozygosity with a loss-of-function variant, co-segregation with the phenotype in the family, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.