rs111033257

Positions:

chr7-107700162-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_SupportingPP4PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold ≤0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID:19204907, 31599023).This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID:19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID:9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID:14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA261418/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 2.97

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 Likely_pathogenic. Variant got 7 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1694G>A	p.Cys565Tyr	missense_variant	15/21	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.1694G>A	p.Cys565Tyr	missense_variant	15/21		NM_000441.2	ENSP00000494017	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000938

AC:

AN:

1386592

Hom.:

Cov.:

AF XY:

0.00000432

AC XY:

AN XY:

694518

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000115

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000516

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 30, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2024	Variant summary: SLC26A4 c.1694G>A (p.Cys565Tyr) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250542 control chromosomes (gnomAD). c.1694G>A has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss with enlarged vestibular aqueduct who were compound heterozygous with pathogenic/likely pathogenic variants (van Hauwe_1998, Tsukamoto_2003, Choi_2009). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a significant reduction in transport activity (Choi_2009, Wasana_2020). The following publications have been ascertained in the context of this evaluation (PMID: 9618166, 14508505, 19204907, 31599023). ClinVar contains an entry for this variant (Variation ID: 43519). A ClinGen expert panel has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jul 19, 2023	The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold less than or equal to 0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID: 19204907, 31599023). This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID: 19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID: 9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID: 14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023). -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 565 of the SLC26A4 protein (p.Cys565Tyr). This variant is present in population databases (rs111033257, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SLC26A4-related conditions (PMID: 9618166, 14508505, 19204907, 26346818). 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: 43519). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 19204907, 20826203, 28341401, 33801843). This variant disrupts the p.Cys565 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 16570074), 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:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Affects, no assertion criteria provided	in vitro;literature only	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

The Cys565Tyr variant (SLC26A4) has been reported in one individual with Pendred syndrome and one individual with nonsyndromic hearing loss with enlarged vestib ular aqueducts (EVA), both of whom carried a second SLC26A4 variant, and was abs ent in 192 control chromosomes (Van Hauwe 1998, Tsukamoto 2003). In addition, th is variant has been identified in one individual with SNHL and EVA by our labora tory, who also carried a second pathogenic SLC26A4 variant. Studies have shown t hat the Cys565Tyr variant does not appear to impact certain protein functions (C hoi 2009, Ishihara 2010). However, these in vitro assays may not accurately repr esent biological function or fully assess all functions of the protein. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish the pathogenicity of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

0.57

D;D;D;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.055

T;.

Polyphen

0.59

P;P

Vest4

0.45

MVP

0.98

MPC

0.021

ClinPred

0.84

GERP RS

4.6

Varity_R

0.46

gMVP

0.71

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