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

gnomAD frequency: 0.00083  dbSNP: rs111033243

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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).
Eurofins Ntd Llc (ga)	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.
Mendelics	RCV000987940	SCV001137436	likely benign	Pendred syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000756644	SCV001145683	uncertain significance	not provided	2019-12-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987940	SCV001321508	uncertain significance	Pendred syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001004634	SCV001321509	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000987940	SCV001712300	uncertain significance	Pendred syndrome	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000756644	SCV001817982	likely benign	not provided	2021-06-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32747562, 28444304, 27861301, 26764160, 26226137, 33152970, 33199029, 21045265, 25262649, 31599023, 30245029, 15355436, 26894580, 28941661, 27771369, 23280318, 16570074, 23965030, 19017801, 19509082, 22116359)
CeGaT Center for Human Genetics Tuebingen	RCV000756644	SCV001962084	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001004634	SCV002027118	likely benign	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV000756644	SCV003264642	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 354 of the SLC26A4 protein (p.Phe354Ser). This variant is present in population databases (rs111033243, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with non-syndromic deafness and/or Pendred syndrome (PMID: 15355436, 26894580, 32747562). This variant is also known as F355S. ClinVar contains an entry for this variant (Variation ID: 43492). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 19509082, 22116359). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000756644	SCV003825642	uncertain significance	not provided	2021-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036423	SCV003844846	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1061T>C (p.Phe354Ser) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 1614856 control chromosomes, including 6 homozygotes, predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD v4 database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00055 vs 0.0035), allowing no conclusion about variant significance, although the presence of 6 homozygotes is not suggestive of a highly penetrant variant associated with an autosomal recessive disorder. c.1061T>C has been reported in the literature in several compound heterozgyous and homozygous individuals with SLC26A4-related disorders (e.g. Blons_2004, Franze_2016, Wolf_2017, Bademci_2016), however no co-segregation data was reported. The variant has also been reported in multiple heterozygous individuals affected with non-syndromic hearing loss without other features of Pendred Syndrome (e.g. Albert_2006, Dai_2009, Landa_2013, Chouchen_2021), and in individuals with autoimmune thyroid diseases (Graves' Disease and Hashimoto's Thyroiditis) (e.g. Kallel_2013); however no second SLC26A4 variant was identified in these cases. These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function (e.g. Dai_2009, Dossena_2011, Wasano_2020). These studies found that the variant had similar Cl-/OH- and I-/Cl- transport activity to the WT protein, but had conflicting results with respect to HCO3-/Cl- exchange, with at least one study reporting an approximately 70% reduction in transport activity and another identifying no impairment. The following publications have been ascertained in the context of this evaluation (PMID: 32747562, 16570074, 30245029, 26226137, 15355436, 33199029, 19509082, 22116359, 26894580, 23280318, 23965030, 31599023, 27861301). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 7; likely benign, n = 5; likely pathogenic, n = 1; other, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003952415	SCV004769715	likely benign	SLC26A4-related condition	2019-07-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004634	SCV000994879	other	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	Benign effect in vitro experiment
Clinical Genetics, Academic Medical Center	RCV000756644	SCV001923817	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000756644	SCV001955341	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000756644	SCV001966483	likely benign	not provided		no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV001004634	SCV002059886	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-08-01	flagged submission	research	SLC26A4 c.1061T>C, p.F354S alters a highly conserved residue of SLC26A4 that is predicted to weaken a transmembrane domain. The variant is homozygous in 4 Palestinian children with pre-lingual severe to profound hearing loss (Abu Rayyan 2020). It is present in 5 of 1300 Palestinian controls, as a heterozygote, and present in 164/282612 alleles on gnomAD, all heterozygotes.