7-107672245-G-T

Position:

chr7-107672245-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4PP1_ModeratePS3_SupportingPP4PP3PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID:17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID:25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID:12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID:12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID:11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253312/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

12

6

1

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 4.29

Variant links:

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]

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.412G>T	p.Val138Phe	missense_variant	4/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.412G>T	p.Val138Phe	missense_variant	4/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000440056.1 linkuse as main transcript			downstream_gene_variant		4		ENSP00000394760

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

28

AN:

151896

Hom.:

0

Cov.:

31

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000175

AC:

44

AN:

251236

Hom.:

0

AF XY:

0.000162

AC XY:

22

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000268

AC:

379

AN:

1412074

Hom.:

1

Cov.:

24

AF XY:

0.000257

AC XY:

181

AN XY:

705508

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.000193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.000332

Gnomad4 OTH exome

AF:

0.000222

GnomAD4 genome

AF:

0.000184

AC:

28

AN:

152014

Hom.:

0

Cov.:

31

AF XY:

0.000121

AC XY:

9

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000235

Hom.:

0

Bravo

AF:

0.000204

TwinsUK

AF:

0.000539

AC:

2

ALSPAC

AF:

0.00

AC:

0

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.000206

AC:

25

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	-	in compound heterozygosis with the c.554G>C variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000441.1(SLC26A4):c.412G>T(V138F) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 19204907, 15355436, 11375792, 21551164, 15689455, 12788906, 23273637, 19017801, 9618167, 11932316, 9070918 and 9618166. Classification of NM_000441.1(SLC26A4):c.412G>T(V138F) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 19, 2018	The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID: 17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID: 12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2024	Variant summary: SLC26A4 c.412G>T (p.Val138Phe) 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 0.00018 in 251236 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00018 vs 0.0035), allowing no conclusion about variant significance. c.412G>T has been reported in the literature in multiple individuals affected with Pendred Syndrome (example: Mey_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31633822). ClinVar contains an entry for this variant (Variation ID: 4835). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	Published functional studies demonstrate a damaging effect due to aberrant protein processing, with retention of pendrin in the endoplasmic reticulum and absence of proper pendrin assembly at the cell membrane (Taylor et al., 2002); Common variant in Caucasian populations, accounting for approximately 12% of pathogenic alleles in published studies of Western European individuals (Tsukada et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (Oza et al., 2018; ClinVar SCV000840515.3; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9618166, 21551164, 17503324, 23336812, 19608655, 11932316, 26969326, 23273637, 12788906, 26744121, 29986705, 30473558, 30762457, 29320412, 29984802, 27771369, 18285825, 26683941, 25999548, 24224479, 16570074, 15689455, 23965030, 20597900, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the SLC26A4 protein (p.Val138Phe). This variant is present in population databases (rs111033199, gnomAD 0.03%). This missense change has been observed in individuals with Pendred syndrome (PMID: 9618166, 11932316, 12788906, 21551164, 23273637, 24224479, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4835). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2018	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 21, 2021	PM3_Very_Strong, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4, PS3_Supporting -

SLC26A4-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 14, 2024	The SLC26A4 c.412G>T variant is predicted to result in the amino acid substitution p.Val138Phe. This variant has been reported to be causative for Pendred syndrome (Van et al. 1998. PubMed ID: 9618166; Borck et al. 2003. PubMed ID: 12788906; de Moraes et al. 2013. PubMed ID: 23273637). Functional studies show this variant results in loss of proper localization of the SLC26A4 protein to the cell membrane (Taylor et al. 2002. PubMed ID: 11932316). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of the available literature, the SLC26A4 c.412G>T (p.Val138Phe) missense variant has been identified in a total of 23 patients with hearing loss or Pendred syndrome, including in four in a homozygous state, 14 in a compound heterozygous state and five in a heterozygous state in whom a second variant was not identified. The variant was also found in a heterozygous state in at least two unaffected family members (Van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Gonzales-Trevino et al. 2001; Taylor et al. 2002; Borck et al. 2003; Pryor et al. 2005; Pera et al. 2008; Kandasamy et al. 2011; Landa et al. 2013). Segregation with disease is reported to have been shown in several families (Van Hauwe et al. 1998; Gonzales-Trevino et al. 2001). The variant was absent from 214 controls and is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Val138 residue is conserved among several other related sulfate transporter genes from different species. Functional studies have shown that the p.Val138Phe variant protein is retained in the endoplasmic reticulum and fails to reach the cell membrane leading to loss of protein activity (Taylor et al. 2002). Based on the collective evidence, the p.Val138Phe variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Supporting, PM5_Moderate, PP3_Supporting -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2020

The p.Val138Phe variant in SLC26A4 has been reported in more than 20 individuals with clinical features of Pendred syndrome or DFNB4 hearing loss, at least 10 of whom were homozygous or compound heterozygous (Borck 2003 PMID: 12788906, Campbell 2001 PMID: 11317356, Coyle 1998 PMID: 9618167, de Moraes 2013 PMID: 23273637, Gonzalez Trevino 2001 PMID: 11375792, Kandasamy 2011 PMID: 21551164, Pourova 2010 PMID: 20597900, Pryor 2005 PMID: 15689455, Taylor 2002 PMID: 11932316, Van Hauwe 1998 PMID: 9618166, LMM data). It has been identified in 0.03% (38/126540) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs111033199); however, this low frequency is consistent with the carrier frequency in the general population. In vitro functional studies provide some evidence that the p.Val138Phe variant may impact protein function (Taylor 2002 PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for Pendred syndrome or nonsyndromic hearing loss in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_VeryStrong, PS4, PM2_Supporting, PS3_Supporting. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.24

D

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.42

D

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

A

PrimateAI

Uncertain

0.60

T

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.91

MVP

0.99

MPC

0.012

ClinPred

0.25

T

GERP RS

5.1

Varity_R

0.83

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111033199; hg19: chr7-107312690;