rs111033309

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000441.2(SLC26A4):c.2015G>A(p.Gly672Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000157 in 1,609,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G672V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 4.25

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 16 ACMG points.

PM1

In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000441.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107702038-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 7-107702038-G-A is Pathogenic according to our data. Variant chr7-107702038-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107702038-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2015G>A	p.Gly672Glu	missense_variant	Exon 17 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.2015G>A	p.Gly672Glu	missense_variant	Exon 17 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000492030.2 link	n.302G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5
SLC26A4	ENST00000644846.1 link	n.725G>A		non_coding_transcript_exon_variant	Exon 7 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000480841.5 link	n.*154G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251180

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000163

AC:

238

AN:

1457610

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

725402

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.00

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:

0.000199

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:7

Feb 21, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2022

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.2015G>A (p.Gly672Glu) results in a non-conservative amino acid change located in the STAS domain 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 6.4e-05 in 251180 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.2015G>A has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that G672E abolished normal protein function at the cell surface (Taylor_2002). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The SLC26A4 c.2015G>A (p.G672E) variant has been observed in the homozygous or compound heterozygous state in 3 families with Pendred syndrome or a dilated vestibular aqueduct (PMID: 9618167;11317356). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC26A4 c.2015G>A (p.Gly672Glu) missense variant has been reported in two studies and is found in a total of seven probands from three families, including two in a homozygous state and five in a compound heterozygous state (Coyle et al. 1998; Campbell et al. 2011). All probands had clinical features of Pendred syndrome, including hearing loss and temporal bone abnormalities. The variant was absent from 150 control chromosomes and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Taylor et al. (2002) performed functional studies on the p.Gly672Glu variant and found that the localization of the variant protein to the membrane is partial, and the function of the protein that reached the cell surface was abolished. Based on the collective evidence, the p.Gly672Glu variant is classified as pathogenic for Pendred syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 15, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the p.(G672E) variant abolishes normal protein function (Taylor et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9618167, 11317356, 33199029, 21366435, 32165640, 11932316) -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 672 of the SLC26A4 protein (p.Gly672Glu). This variant is present in population databases (rs111033309, gnomAD 0.01%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 9618167, 11317356, 21366435). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43532). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic. -

SLC26A4-related disorder

Pathogenic:2

Jul 25, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM3, PP1, PP3 -

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC26A4 c.2015G>A variant is predicted to result in the amino acid substitution p.Gly672Glu. This variant has been reported to be causative for Pendred syndrome (Coyle et al. 1998. PubMed ID: 9618167; Campbell et al. 2001. PubMed ID: 11317356). Functional studies showed that this variant had reduced localization to the cell surface and abolished iodide efflux in an in vitro assay (Taylor et al. 2002. PubMed ID: 11932316). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 07-17-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Feb 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly672Glu variant in SLC26A4 has been reported in 3 probands with the clin ical features of Pendred syndrome, and was identified by our laboratory in 1 ind ividual with hearing loss and EVA. The variant segregated with Pendred syndrome or hearing loss in 4 affected family members across 3 families, and all affected individuals were either homozygous for this variant or carried a second SLC26A4 variant (Coyle 1998, Campbell 2001, LMM unpublished data). In addition, functio nal analysis revealed that this variant causes the protein to be retained in the cytoplasm and abolishes its normal function at the cell surface (Taylor 2002). This variant was also identified in 5/66278 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033309); however, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Gly672Glu variant meets our criteria to be classifi ed as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.9

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.2

D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0080

D;.

Polyphen

0.78

P;P

Vest4

0.82

MVP

0.99

MPC

0.057

ClinPred

0.52

GERP RS

4.7

Varity_R

0.87

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over