rs111033303

Positions:

chr7-107674970-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.626G>T(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,932 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 (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 9.43

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 7-107674970-G-T is Pathogenic according to our data. Variant chr7-107674970-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107674970-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.626G>T	p.Gly209Val	missense_variant	6/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.626G>T	p.Gly209Val	missense_variant	6/21		NM_000441.2	ENSP00000494017	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251470

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

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:

0.000607

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000760

AC:

1111

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000727

AC XY:

529

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000941

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.000362

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000554

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2023	Variant summary: SLC26A4 c.626G>T (p.Gly209Val) 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 0.0003 in 251470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.626G>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pendred Syndrome and non-syndromic deafness (e.g., Campbell_2001, Hutchin_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11317356, 16283880). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000441.1(SLC26A4):c.626G>T(G209V) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: 11932316, 24224479, 15689455, 19509082, 17503324, 9618166, 16570074, 16283880, 18285825 and 10190331. Classification of NM_000441.1(SLC26A4):c.626G>T(G209V) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 06, 2022	PS3, PM3_Strong, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The SLC26A4 c.626G>T (p.G209V) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss. This variant is predicted to change an amino acid that is well-conserved across species (PMID: 10190331; 9618166; 11317356; 11932316; 16570074; 24224479; 26969326; 18285825; 15689455; 15355436). -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 deafness with enlarged vestibular aqueduct (MIM#600791) and 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 (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (85 heterozygotes, 0 homozygotes). (SP) 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 sulfate permease family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over 10 unrelated individuals with SLC26A4-related conditions in both compound heterozygous and homozygous states (ClinVar, LOVD, PMIDs:11317356, 16570074, 19017801, 19204907, 24224479). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	Published functional studies demonstrate a damaging effect on iodide transport (Taylor et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed multiple times with a different pathogenic variant in unrelated patients with features of Pendred syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Campbell et al., 2001; Blons et al., 2004; Albert et al., 2006; Choi et al., 2009; Ladsous et al., 2014; Soh et al., 2015; Cengiz et al., 2017; Roman et al., 2020); This variant is associated with the following publications: (PMID: 31971949, 31589614, 31980526, 24224479, 14679580, 11932316, 10190331, 10700480, 15355436, 19204907, 10861298, 25741868, 27771369, 25394566, 28964290, 18285825, 11317356, 9618166, 19509082, 16570074, 15689455, 16283880, 32853555, 26969326, 20301640) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 209 of the SLC26A4 protein (p.Gly209Val). This variant is present in population databases (rs111033303, gnomAD 0.06%). This missense change has been observed in individuals with Pendred syndrome or deafness (PMID: 9618166, 11317356, 11932316, 16570074, 19204907, 19509082, 21366435, 24224479, 25394566, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4821). 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: 11932316). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SLC26A4: PM3:Very Strong, PM2:Supporting, PP3, PP4, PS3:Supporting -

SLC26A4-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The SLC26A4 c.626G>T (p.Gly209Val) missense variant has been reported in at least eight studies in related and unrelated probands, including one in a homozygous state and 17 in a compound heterozygous state (Van Hauwe et al. 1998; Campbell et al. 2001; Taylor et al. 2002; Pryor et al. 2005; Pera et al. 2008; Ladsous et al. 2014; Soh et al. 2015; Sloan-Heggen et al. 2016). Pera et al. (2008) described two affected siblings who were compound heterozygous for the p.Gly209Val variant and another variant, while their unaffected parents were identified as carriers. The p.Gly209Val variant was absent from 314 controls, but is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. In HeLa cells, the p.Gly209Val variant showed normal cellular localization, but reduced iodide efflux compared to wildtype (Taylor et al. 2002). Based on the collective evidence, this 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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 04, 2024	The SLC26A4 c.626G>T variant is predicted to result in the amino acid substitution p.Gly209Val. This variant has been reported to be causative for Pendred syndrome (Van Hauwe et al. 1998. PubMed ID: 9618166; Ladsous et al. 2014. PubMed ID: 24224479; Albert et al. 2006. PubMed ID: 16570074; Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 11, 2017

The p.Gly209Val variant in SLC26A4 has been reported in at least 15 individuals with hearing loss and EVA (DFNB4) or Pendred syndrome (Van Hauwe 1998, Usami 199 9, Campbell 2001, Pryor 2005, Albert 2006, Pera 2008, LMM data). Many affected i ndividuals were homozygous or compound heterozygous. This variant has been ident ified in 75/126676 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs111033303); however, its frequency is low enough to be consistent with a recessive carrier frequency for Pendred s yndrome or nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4 or Pendred syndrome b ased on the previously reported biallelic occurrence in multiple affected indivi duals, association with specific clinical features, and a low frequency in the g eneral population. ACMG/AMP Criteria applied: PM3_Strong, PS4, PP4. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.9

D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

1.0

MVP

0.99

MPC

0.075

ClinPred

0.94

GERP RS

5.6

Varity_R

0.99

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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