NM_000441.2:c.1061T>C

Variant names:

• chr7-107689112-T-C
• rs111033243
• NM_000441.2:c.1061T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS3 BS1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1061T>C variant in SLC26A4 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 354 (p.Phe354Ser). The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population which meets the AR threshold (≥0.07%) for BS1_P. Although the REVEL computational prediction analysis tool produced a score of 0.955, PP3 was not applied. It was observed in 3 probands with sensorineural hearing loss, however they were not scored due to the high FAF in gnomAD (PMID:26226137, 32747562, 27861301). Functional studies have shown that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023) meeting BS3. In summary, this variant is likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: BS3, BS1_P (ClinGen Hearing Loss VCEP specifications version 2; 11/28/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA132656/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (6 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:8 B:11 O:1
• Conservation: PhyloP100: 7.17

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1061T>C	p.Phe354Ser	missense_variant	Exon 9 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1061T>C	p.Phe354Ser	missense_variant	Exon 9 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000609 AC: 153 AN: 251206 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135752

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000519 AC: 759 AN: 1461670 Hom.: 6 Cov.: 31 AF XY: 0.000512 AC XY: 372 AN XY: 727136

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000899 AC XY: 67 AN XY: 74486

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.00151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:8 Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4 Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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) -

Dec 16, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC26A4: PP3, BS1 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 18, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1 Uncertain:1 Benign:1 Other:1

Aug 20, 2019

National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center

Significance: other

Review Status: no assertion criteria provided

Collection Method: in vitro;literature only

Benign effect in vitro experiment Benign effect in vitro experiment

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 01, 2020

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pendred syndrome Uncertain:2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:2

Dec 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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). -

Nonsyndromic genetic hearing loss Benign:1

Nov 28, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1061T>C variant in SLC26A4 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 354 (p.Phe354Ser). The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population which meets the AR threshold (>=0.07%) for BS1_P. Although the REVEL computational prediction analysis tool produced a score of 0.955, PP3 was not applied. It was observed in 3 probands with sensorineural hearing loss, however they were not scored due to the high FAF in gnomAD (PMID: 26226137, 32747562, 27861301). Functional studies have shown that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023) meeting BS3. In summary, this variant is likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: BS3, BS1_P (ClinGen Hearing Loss VCEP specifications version 2; 11/28/2023) -

SLC26A4-related disorder Benign:1

Jul 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.93
MVP		0.99
MPC		0.074
ClinPred		0.060	T
GERP RS		5.6
Varity_R		0.95
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033243; hg19: chr7-107329557;