rs111033205

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

The NM_000441.2(SLC26A4):c.85G>C(p.Glu29Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,557,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E29D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 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:20

Conservation

PhyloP100: 2.63

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:

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

SLC26A4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain 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 chr7-107661728-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065202.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 7-107661726-G-C is Pathogenic according to our data. Variant chr7-107661726-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107661726-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.34593493). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.85G>C	p.Glu29Gln	missense_variant	2/21	ENST00000644269.2
SLC26A4-AS1	NR_028137.1 linkuse as main transcript	n.73C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.85G>C	p.Glu29Gln	missense_variant	2/21		NM_000441.2	P1	O43511-1
SLC26A4-AS1	ENST00000668981.1 linkuse as main transcript	n.133C>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152238

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000926

AC:

AN:

162000

Hom.:

AF XY:

0.0000572

AC XY:

AN XY:

87366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000200

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.000217

GnomAD4 exome

AF:

0.000158

AC:

222

AN:

1405620

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

113

AN XY:

694860

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000267

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000950

Gnomad4 NFE exome

AF:

0.000195

Gnomad4 OTH exome

AF:

0.0000854

GnomAD4 genome

AF:

0.000105

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000289

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000770

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	Published functional studies demonstrate a damaging effect due to reduced iodide transport activity (Pera et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14679580, 29372807, 24224479, 11317356, 15099345, 15355436, 16950989, 18285825, 20597900, 23336812, 17503324, 19017801, 16570074, 31589614, 34426522, 34170635, 33199029, 31541171, 36499699) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 16, 2022	PM2_supporting, PM3_very_strong, PS3_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 29 of the SLC26A4 protein (p.Glu29Gln). This variant is present in population databases (rs111033205, gnomAD 0.03%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 11317356, 15355436, 16570074, 20597900, 25394566). ClinVar contains an entry for this variant (Variation ID: 4839). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19017801). This variant disrupts the p.Glu29 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 22285650, 25372295), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -

Pendred syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 09, 2019	- -

Wolff-Parkinson-White pattern

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

SLC26A4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 24, 2018

Across a selection of the available literature, the SLC26A4 c.85G>C (p.Glu29Gln) missense variant has been reported in at least nine studies in which it was identified in a total of 18 individuals, including in a compound heterozygous state in 14 individuals, in a heterozygous state in three individuals, in a double heterozygous state in one individual and in one individual with unknown zygosity. Affected individuals were diagnosed with either Pendred syndrome, an autosomal recessive form of deafness, or enlarged vestibular aqueduct or Mondini dysplasia (Campbell et al. 2001; Prasad et al. 2004; Blons et al. 2004; Alberts et al. 2006; Yang et al. 2007; Pera et al. 2008; Pourova et al. 2010; Rendtorff et al. 2013; Ladous et al. 2014). The p.Glu29Gln variant was found to segregate in at least one study (Yang et al. 2007). The variant was absent from 469 controls and is reported at a frequency of 0.000229 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using fluorimetric measurements showed that the p.Glu29Gln variant protein has reduced chloride/iodide transport (Pera et al. 2008). Based on the collective evidence, the p.Glu29Gln 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. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 14, 2015

The p.Glu29Gln variant in SLC26A4 has been identified in multiple individuals wi th hearing loss and temporal bone abnormalities including over 15 probands who w ere compound heterozygous with another pathogenic variant in SLC26A4, and it has segregated in three affected siblings (Albert 2006, Campbell 2001, Gardner 2006 , Ladsous 2014, Pera 2008, Pourova 2010, Rendtorff 2013, LMM unpublished data). Functional studies have demonstrated that this variant impacts the protein func tion (Pera 2008). In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 nonsyndromic hearing loss or Pendred syndrome in an auto somal recessive manner. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.74

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

0.93

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

N;.;N

REVEL

Uncertain

0.64

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.17

T;.;T

Polyphen

0.66

P;P;.

Vest4

0.72

MVP

0.96

MPC

0.021

ClinPred

0.22

GERP RS

4.2

Varity_R

0.41

gMVP

0.65

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