rs111033307

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.1334T>G(p.Leu445Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,612,682 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L445L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 7.15

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000441.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 7-107694473-T-G is Pathogenic according to our data. Variant chr7-107694473-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107694473-T-G is described in Lovd as [Likely_pathogenic]. Variant chr7-107694473-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1334T>G	p.Leu445Trp	missense_variant	11/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1334T>G	p.Leu445Trp	missense_variant	11/21		NM_000441.2	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000997

AC:

AN:

250764

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

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:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1460498

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000102

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000441.1(SLC26A4):c.1334T>G(L445W) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18285825, 15355436, 24224479, 9618166, 19204907, 16570074, 20128824 and 23273637. Classification of NM_000441.1(SLC26A4):c.1334T>G(L445W) 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	Baylor Genetics	-	- -
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 leucine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 28 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 sulfate permease (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with either deafness with enlarged vestibular aqueduct (MIM#600791) or Pendred syndrome (MIM#274600) and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 24224479, 26752218). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS ID# 21G002172). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Pathogenic:6

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	Revvity Omics, Revvity	Apr 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 445 of the SLC26A4 protein (p.Leu445Trp). This variant is present in population databases (rs111033307, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Pendred syndrome (PMID: 9618166, 19204907, 20128824, 24224479, 26752218). ClinVar contains an entry for this variant (Variation ID: 4829). 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: 19204907, 20128824, 26752218). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2015	The L445W missense variant has been reported previously in association with Pendred syndrome (Van Hauwe et al., 1998; Choi et al., 2009). In vitro functional studies demonstrated that the presence of the L445W variant resulted in the loss of glycosylation of the pendrin protein (Rebeh et al., 2010). We interpret the L445W variant as pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:4Other:1

Affects, no assertion criteria provided	clinical testing;in vitro	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 27, 2010

The p.Leu445Trp variant has been frequently reported in the literature and is kn own to be associated with the clinical features of DFNB4/Pendred syndrome (Van H auwe 1998, Cama 2009, Choi 2009, Kahrizi 2009, Lopez-Bigas 2001, Masmoudi 2000, Pera 2008, Wilch 2006). Therefore, this variant meets our criteria to be classif ied as pathogenic for DFNB4/Pendred syndrome in an autosomal recessive manner. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Benign

0.96

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;H

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.99

MPC

0.074

ClinPred

0.96

GERP RS

5.9

Varity_R

0.96

gMVP

0.88

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