7-107710135-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.2171A>G(p.Asp724Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000348 in 1,609,138 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. D724N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.10

Publications

6 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: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000441.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107710134-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 553188.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 7-107710135-A-G is Pathogenic according to our data. Variant chr7-107710135-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2171A>G	p.Asp724Gly	missense_variant	Exon 19 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC26A4	ENST00000644269.2 link	c.2171A>G	p.Asp724Gly	missense_variant	Exon 19 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000644846.1 link	n.*73A>G		non_coding_transcript_exon_variant	Exon 8 of 10			ENSP00000494344.1
SLC26A4	ENST00000644846.1 link	n.*73A>G		3_prime_UTR_variant	Exon 8 of 10			ENSP00000494344.1
SLC26A4	ENST00000492030.2 link	n.377-20A>G		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251296

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1456904

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

725178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

1107528

Other (OTH)

AF:

0.0000332

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 11, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on iodide transport (PMID: 19017801); 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: 18285825, 27344577, 20668687, 24224479, 14679580, 25491636, 19509082, 15811013, 15355436, 24860705, 19017801, 31589614, 33199029, 36515421)

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 724 of the SLC26A4 protein (p.Asp724Gly). This variant is present in population databases (rs757820624, gnomAD 0.004%). This missense change has been observed in individual(s) with Pendred syndrome or nonsyndromic enlarged vestibular aqueduct (PMID: 14679580, 15811013, 24224479). 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: 228396). 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: 19017801). This variant disrupts the p.Asp724 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 15355436, 27344577), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

May 30, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pendred syndrome

Pathogenic:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 24, 2018

Counsyl

Significance:Likely pathogenic

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.

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Feb 09, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC26A4-related disorder

Pathogenic:1

Dec 03, 2018

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A4 c.2171A>G (p.Asp724Gly) missense variant has been reported in at least three studies and is found in a total of four probands, including three probands in a compound heterozygous state and one proband in a heterozygous state (Prasad et al. 2004; Pera et al. 2008; Ladsous et al. 2014). Of the three compound heterozygous probands; two probands were clinically diagnosed with Pendred syndrome and one proband was noted to have non-syndromic enlarged vestibular aqueduct. The heterozygous proband was described to have non-syndromic hearing loss, although an alternate etiology was suspected to be causative, this phenotype and thus this proband was considered a coincidental carrier of the p.Asp724Gly variant (Pera et al. 2008). The p.Asp724Gly variant was reported in two of 648 controls alleles and is reported at a frequency of 0.000032 in the European (non-Finnish) population of the Genome Aggregation Database. The Asp724 residue is highly conserved. The p.Asp724Gly variant protein was expressed in HEK-293 phoenix cells and had no detectable iodide transport when analyzed with fluorometry, indicating complete inactivation in comparison to wildtype (Pera et al. 2008). Based on the evidence, the p.Asp724Gly 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.

Rare genetic deafness

Pathogenic:1

Oct 30, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp724Gly variant in SLC26A4 has been previously reported in three individuals with hearing loss and EVA or Pendred syndrome who were compound heterozygous with a pathogenic variant (Prasad 2004, Arellano 2005, Ladsous 2014). A different missense variant at the same position (p.Asp724Asn) has also been reported in one individual with Pendred syndrome who was compound heterozygous for a second pathogenic variant (Blons 2004). In addition, in vitro functional studies suggest the variant impairs the normal function of the protein (Pera 2008), and computational and conservation analysis support a deleterious effect. The variant has also been identified in 0.008% (2/24966) of African chromosomes by gnomAD; however this frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp724Gly variant is likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Supporting, PP4, PP3.

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Apr 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.0

.;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

7.1

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.9

D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Vest4

0.97

ClinPred

0.98

GERP RS

5.5

Varity_R

0.96

gMVP

0.90

Mutation Taster

=2/98

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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