ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1061T>C (p.Phe354Ser) (rs111033243)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036423 SCV000060078 likely benign not specified 2017-08-03 criteria provided, single submitter clinical testing p.Phe354Ser in exon 9 of SLC26A4: This variant is not expected to have clinical significance due to equal frequencies in probands with hearing loss and controls and the fact that none of the probands had a variant affecting the other allele (Albert 2006, Dai 2009, Pera 2008, LMM data). This variant was also identified in equal frequency among patients with Graves' and/or Hashimoto's thyroiditis bu t no history of hearing loss (4/237) and in matched controls (5/206) (Hadj-Kacem 2010). In vitro functional studies have shown that this variant did not impact protein function (Dossena 2011). In addition, this variant has been identified i n 0.15% (51/34394) of Latino chromosomes and 78/126480 European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033243).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000036423 SCV000340307 likely benign not specified 2016-03-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756644 SCV000884522 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing The p.Phe354Ser variant (rs111033243) has been studied extensively due to a possible role in Pendred syndrome (PS) and deafness with enlarged vestibular aqueduct (EVA); conflicting evidence has emerged. Firstly, the p.Phe354Ser variant has been observed as a homozygote in a patient included in a cohort of autosomal recessive nonsyndromic deafness (ARNSD) patients (Bademci 2016), and was observed in trans with a pathogenic SLC26A4 variant in a patient included in a PS cohort (Blons 2004; reported as p.Phe355Ser). However, it has also been found at a similar frequency in patient and control populations (Hadj-Kacem 2010), and has even been found in controls while being absent from absent from a hearing impaired population (Pera 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.05 percent (identified on 159 out of 276,944 chromosomes). Data concerning the effect of the p.Phe354Ser variant on SLC26A4 protein function are also mixed, with some studies suggesting no effect on solute transport (Dossena 2011), while others suggesting a decrease in Cl-/HC03- exchange activity (Dai 2009). Moreover, the phenylalanyl at codon 354 is highly conserved considering 11 species up to chicken and there is a large physiochemical difference with the substituted serine (Alamut software v2.9.0). Thus, based on the available information, the clinical significance of the p.Phe354Ser variant cannot be determined with certainty.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.