rs542620119

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3_SupportingPM3PP3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.554G>A variant in SLC26A4 is a missense variant predicted to cause substitution of arginine by threonine at amino acid 185 (p.Arg185Thr). The variant was present in 0.0165% (1/6062) of Middle Eastern alleles, which is the highest population minor allele frequency in gnomAD v4.1.0, and PM2_Supporting was applied at the recommendation of the expert panel. This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as in three probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID:24051746, 20597900, 22285650, 34680964). The variant was also observed in one proband with limited phenotype information and no second variant identified (PMID:31387071). Additionally, it was observed in one proband with hearing loss, enlarged vestibular aqueduct, and Mondini malformation who was compound heterozygous with a second pathogenic variant with phase unknown (PMID:34599368). The variant was also seen in an infant with mild congenital bilateral sensorineural hearing loss who also had two pathogenic OTOG variants in trans (Invitae internal data ClinVar SCV002243689.3). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID:22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3, PS3_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274070/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 9.44

Publications

5 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.

PS3

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.

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.554G>C	p.Arg185Thr	missense_variant	Exon 5 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.554G>C	p.Arg185Thr	missense_variant	Exon 5 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000915

AC:

AN:

251456

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1111844

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000394

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41540

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.000140

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:4

Apr 04, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC26A4 c.554G>C (p.Arg185Thr) 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 9.1e-05 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (9.1e-05 vs 0.0035), allowing no conclusion about variant significance. c.554G>C has been reported in the literature in individuals affected with clinical features of Pendred Syndrome (example, Pourova_2010, Cirello_2012, Chattaraj_2013, Lenarduzzi_2019, Batissoco_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in predominantly intracellular localization and a partial glycosylation defect resulting in impaired chloride and iodide ion transport in-vitro (example, Cirello_2012, Chattaraj_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (LP/P, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

in compound heterozygosis with the c.412G>T variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic) -

Jul 10, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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. -

Oct 16, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.554G>A variant in SLC26A4 is a missense variant predicted to cause substitution of arginine by threonine at amino acid 185 (p.Arg185Thr). The variant was present in 0.0165% (1/6062) of Middle Eastern alleles, which is the highest population minor allele frequency in gnomAD v4.1.0, and PM2_Supporting was applied at the recommendation of the expert panel. This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as in three probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650, 34680964). The variant was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Additionally, it was observed in one proband with hearing loss, enlarged vestibular aqueduct, and Mondini malformation who was compound heterozygous with a second pathogenic variant with phase unknown (PMID: 34599368). The variant was also seen in an infant with mild congenital bilateral sensorineural hearing loss who also had two pathogenic OTOG variants in trans (Invitae internal data ClinVar SCV002243689.3). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3, PS3_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) -

not provided

Pathogenic:2

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 185 of the SLC26A4 protein (p.Arg185Thr). This variant is present in population databases (rs542620119, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (PMID: 20597900, 22285650, 24051746, 31387071, 34599368). 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: 188878). 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 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 22285650, 24051746). For these reasons, this variant has been classified as Pathogenic. -

May 23, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Mar 14, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2024

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as likely pathogenic for DFNB4. The following ACMG Tag(s) were applied: PM2_Supporting; PM3 (PMID: 24051746); PP3_moderate; PS3_Supporting (PMID: 22285650; 24051746). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Rare genetic deafness

Pathogenic:1

Jan 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg185Thr variant in SLC26A4 has been previously reported in three individ uals with hearing loss and enlarged vestibular aqueducts, including one individu al who was compound heterozygous for a second pathogenic variant in the SLC26A4 gene (Chattaraj 2013, Cirello 2012, Pourova 2010). This variant has been identif ied in 12/66734 (0.02%) of European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs542620119); however, this fre quency is low enough to be consistent with a recessive carrier frequency. In vit ro functional studies reveal that the variant results in abnormal cellular local ization of the protein and significant reduction in its normal functional activi ty (Cirello 2012, Chattaraj 2013), supporting a deleterious effect for this vari ant. In addition, computational tools and conservation analyses predict that the p.Arg185Thr variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic. -

SLC26A4-related disorder

Pathogenic:1

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred syndrome, including in a compound heterozygous state in one and in a heterozygous state in two (Pourova et al. 2010; Cirello et al. 2012; Chattaraj et al. 2013). One of the heterozygotes was also heterozygous for a missense variant in the FOXI1 gene, which is said to display digenic inheritance with SLC26A4. The p.Arg185Thr variant is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells, HEK293 phoenix cells and Xenopus oocytes have demonstrated the variant results in a trafficking defect, altered maturation, and reduced function compared to wildtype. Based on the collective evidence, the p.Arg185Thr variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.73

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

H;H

PhyloP100

9.4

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.96

MVP

1.0

MPC

0.075

ClinPred

0.97

GERP RS

5.1

Varity_R

0.82

gMVP

0.89

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

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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