NM_000441.2:c.2168A>G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000441.2(SLC26A4):c.2168A>G(p.His723Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000653 in 1,609,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25O:1

Conservation

PhyloP100: 7.10

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.

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;

PP5

Variant 7-107710132-A-G is Pathogenic according to our data. Variant chr7-107710132-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107710132-A-G is described in Lovd as [Pathogenic]. Variant chr7-107710132-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2168A>G	p.His723Arg	missense_variant	Exon 19 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.2168A>G	p.His723Arg	missense_variant	Exon 19 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000644846.1 link	n.*70A>G		non_coding_transcript_exon_variant	Exon 8 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000644846.1 link	n.*70A>G		3_prime_UTR_variant	Exon 8 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000492030.2 link	n.377-23A>G		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152254

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:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251294

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000659

AC:

AN:

1456722

Hom.:

Cov.:

AF XY:

0.0000662

AC XY:

AN XY:

725090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00232

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000949

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:10Other:1

May 12, 2020

The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 32 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated STAS domain (DECIPHER, Uniprot). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is prevalent in individuals with Asian descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 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.2168A>G (p.His723Arg) 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 0.00012 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.2168A>G has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss (e.g. Sagong_2012, Jung_2016). These data indicate that the variant is very likely to be associated with disease. Fifteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000441.1(SLC26A4):c.2168A>G(H723R) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18310264, 24007330, 20826203 and 17718863. Classification of NM_000441.1(SLC26A4):c.2168A>G(H723R) 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. -

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:7

Jul 01, 2017

Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2019

National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

in vitro experiment -

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2019

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004825, PMID:9618166, PS1_S).A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000949741, PMID:19040761,24599119, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000113, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Sep 22, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, 1998; Ishihara, 2010; Sagong, 2013; Asakura, 2010; Li, 2016). Lee (2014) noted that patients with two copies of the p.His723Arg variant had poorer hearing and higher proportion of incomplete cochlear turns (Mondini structures) compared to compound heterozygotes with a single copy and a different SLC26A4 variant. Cell-based and biochemical experiments further demonstrated that p.His723Arg polypeptides are impaired at reaching the plasma membrane and exhibit abnormal ion exchange activity that can be rescued at low temperature (Yoon, 2008). This variant is listed in the Genome Aggregation Database (gnomAD) in the East Asian population at a frequency of 0.16 percent (identified on 31 out of 18,868 chromosomes with 0 homozygotes) and is reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 4825). The histidine at position 723 is highly conserved across 12 species (Alamut v2.9.0), and computational analyses of the effects of the p.His723Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether the p.His723Arg variant is pathogenic. -

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with intracellular retention and decreased protein activity in comparison to wild type (Yoon et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20842945, 19786220, 20583162, 23705809, 25266519, 22884721, 20826203, 23469187, 23755160, 24224479, 9618166, 27176802, 28583500, 27082237, 30693673, 32477112, 31599023, 34943631, 34943614, 11405873, 24007330, 22975760, 11502831, 21961810, 24338212, 26035154, 26100058, 26346818, 27384033, 26763877, 28990112, 28981942, 28786104, 28964290, 27374754, 28802383, 29234782, 28093008, 28052261, 17322586, 30282152, 29447821, 30589569, 30036422, 30733538, 31347505, 30842343, 31564438, 29650690, 31541171, 31827275, 32203226, 30896630, 32425884, 30275481, 32877901, 34170635, 32447495, 15905611, 32459320, 32645618, 32536503, 33597575, 33724713, 34006472, 35204885, 35276235, 35114279, 34801268, 35249537, 34545167, 18310264) -

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 723 of the SLC26A4 protein (p.His723Arg). This variant is present in population databases (rs121908362, gnomAD 0.2%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11405873, 17322586, 20583162, 22884721, 23705809, 24338212). 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: 4825). 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) indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 20583162). For these reasons, this variant has been classified as Pathogenic. -

SLC26A4-related disorder

Pathogenic:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg 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. -

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC26A4 c.2168A>G variant is predicted to result in the amino acid substitution p.His723Arg. This variant has been reported as homozygous or compound heterozygous in patients with hearing loss and enlarged vestibular aqueduct (EVA) or Pendred syndrome (PS) (Van Hauwe et al. 1998. PubMed ID: 9618166; Huang et al. 2011. PubMed ID: 21961810; Ladsous et al. 2014. PubMed ID: 24224479; Sakuma et al. 2016. PubMed ID: 26763877). Functional studies have shown that the p.His723Arg variant results in abnormal cellular localization and ion transport (Yoon et al. 2008. PubMed ID: 18310264; Ishihara et al. 2010. PubMed ID: 20826203; Lee et al. 2014. PubMed ID: 24007330). This variant is reported in 0.16% of alleles in individuals of East-Asian descent in gnomAD, and is reported to be a common pathogenic variant in this population (Yoon et al. 2008. PubMed ID: 18310264; Lee et al. 2014. PubMed ID: 24007330). This variant is interpreted as pathogenic. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP3_Strong -

Jan 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Aug 27, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His723Arg variant in SLC26A4 has been reported in 37 probands with Pendred syndrome (Wu 2005, Van Hauwe 1998, Lee 2008, Asakura 2010, Cho 2006, Dai 2008, Hu 2007, Ishihara 2010, Kim 2009, Park 2003, Reyes 2009, Tsukamoto 2003, Usami 1999, Yoon 2008). Many of these probands were homozygous or compound heterozygous, and the variant has segregated with disease in several families. Furthermore, functional studies revealed that the p.His723Arg variant disrupts the normal cellular localization and ion transport activity of the protein (Yoon 2008, Ishihara 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.1

D;.

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.84

MVP

1.0

MPC

0.076

ClinPred

0.27

GERP RS

5.5

Varity_R

0.96

gMVP

0.91

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.

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