rs397516421

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3_StrongPP3PP4

This summary comes from the ClinGen Evidence Repository: The c.1708G>A variant in SLC26A4 is a missense variant predicted to cause the substitution of valine by isoleucine at amino acid 570 (p.Val570Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computations predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on SLC26A4 function. This variant is located at the first nucleotide of the exon and is heavily conserved in UCSC. Splice prediction analysis using MaxEntScan suggests an impact on splicing from the loss of the 3' consensus splice sequence (PP3). The c.1708G>A (p.Val570Ile) variant in SLC26A4 has also been detected in 3 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe.This variant has been detected in at least 3 individuals with Pendred syndrome. All of these individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (3 PM3 points, PMID:34170635, SCV000060111.6) (PM3_Strong). At least two probands with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PMID:34170635, SCV000060111.6) (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA132675/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:2

Conservation

PhyloP100: 7.68

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Pendred syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM3

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 rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.1708G>A	p.Val570Ile	missense_variant, splice_region_variant	Exon 16 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 link	c.1708G>A	p.Val570Ile	missense_variant, splice_region_variant	Exon 16 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000480841.5 link	n.557G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 8	3
SLC26A4	ENST00000644846.1 link	n.418G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000492030.2 link	n.91-726G>A		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251016

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000300

AC:

AN:

1434714

Hom.:

Cov.:

AF XY:

0.0000419

AC XY:

AN XY:

715664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32938

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00104

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

1087426

Other (OTH)

AF:

0.0000505

AC:

AN:

59412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:2Uncertain:1

Oct 31, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1708G>A variant in SLC26A4 is a missense variant predicted to cause the substitution of valine by isoleucine at amino acid 570 (p.Val570Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computations predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on SLC26A4 function. This variant is located at the first nucleotide of the exon and is heavily conserved in UCSC. Splice prediction analysis using MaxEntScan suggests an impact on splicing from the loss of the 3' consensus splice sequence (PP3). The c.1708G>A (p.Val570Ile) variant in SLC26A4 has also been detected in 3 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe.This variant has been detected in at least 3 individuals with Pendred syndrome. All of these individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (3 PM3 points, PMID: 34170635, SCV000060111.6) (PM3_Strong). At least two probands with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PMID: 34170635, SCV000060111.6) (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022) -

Mar 30, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 02, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC26A4 c.1708G>A (p.Val570Ile) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. Computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes this site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251016 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.1708G>A has been observed in individuals affected with features of Pendred Syndrome (Usami_2008, Tian_2021, Baldyga_2023, Labcorp (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34170635, 36833263, 18368581). ClinVar contains an entry for this variant (Variation ID: 43521). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:2

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 570 of the SLC26A4 protein (p.Val570Ile). This variant is present in population databases (rs397516421, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome and/or deafness (PMID: 34170635; Invitae; ClinVar entry for Variation ID: 43521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43521). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Nov 04, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Classified as likely pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001164268.1; PMID: 30311386); This variant is associated with the following publications: (PMID: 34230634, 34170635, 36833263, 30311386) -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC26A4-related disorder

Pathogenic:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC26A4 c.1708G>A variant is predicted to result in the amino acid substitution p.Val570Ile. This variant resides in the first nucleotide of exon 16 and based on available splicing prediction programs (Alamut Visual v1.6.1) it is predicted to affect splicing by weakening the canonical splice acceptor site. This variant has been reported along with a second pathogenic variant in a patient with hearing loss and enlarged vestibular aqueduct (Tian et al 2021. PubMed ID: 34170635). This variant is reported in 0.080% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is classified as likely pathogenic for autosomal recessive Pendred syndrome by the ClinGen Hearing Loss Variant Curation Expert Panel, in part based on internal data from other clinical testing laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/43521/). In summary, we interpret this variant as likely pathogenic. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Jun 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Sep 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val570Ile variant in SLC26A4 has been identified by our laboratory in two Ashkenazi Jewis h individuals with hearing loss and EVA who also carried a second SLC26A4 varian t of uncertain clinical significance and one individual with hearing loss and Mo ndini dysplasia who did not carry a second pathogenic variant in the SLC26A4 gen e. Moreover, this variant has been identified in one other proband as reported o n the MORL website (www.healthcare.uiowa.edu/labs/pendredandbor/slcMutations.htm ), but was absent from large population studies. The valine (Val) residue at pos ition 570 is highly conserved across species. In addition, the G nucleotide at p osition 1708 is located within the 3? splice junction consensus sequence and the refore could impact splicing (in silico programs suggest a modest divergence fro m consensus). In summary, the clinical significance of the p.Val570Ile variant i s uncertain; however the available data suggest that it is more likely to be pat hogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.39

T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

7.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.85

N;.

REVEL

Uncertain

0.55

Sift

Benign

0.082

T;.

Sift4G

Benign

0.14

T;.

Polyphen

0.97

D;D

Vest4

0.62

MutPred

0.50

Gain of catalytic residue at V570 (P = 0.0182);Gain of catalytic residue at V570 (P = 0.0182);

MVP

0.99

MPC

0.076

ClinPred

0.42

GERP RS

5.7

Varity_R

0.35

gMVP

0.62

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over