rs111033454

Positions:

chr7-107683281-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP4PM2_SupportingPM3_StrongPS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.845G>A (NM_000441.2) variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 282 (p.Cys282Tyr). The highest population minor allele frequency in gnomAD v.2.1.1 is 0.000053 (6/113490 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.0007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.719 which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least 4 individuals with hearing loss. Of those individuals, three were compound heterozygous for the variant and a pathogenic variant observed in trans and one had a rare VUS variant on other allele (c.1001+1G>A, c.233A > G, 3.25 PM3 points, PMID:26969326,33152970, SCV000060163.6, SCV000343642.4) (PM3_Strong). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype highly specific for Pendred syndrome (PP4, PMID:26969326,33152970, SCV000060163.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, PS3_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA261440/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:1

Conservation

PhyloP100: 5.48

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 8 ACMG points.

PS3

PM2

PM3

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.845G>A	p.Cys282Tyr	missense_variant	7/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.845G>A	p.Cys282Tyr	missense_variant	7/21		NM_000441.2	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251138

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135730

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:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461202

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726918

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74464

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Published functional studies demonstrate a reduction in activity in transfected cells compared to wild type (De Moraes et al., 2016).; Reported in individuals with hearing loss who also harbored additional hearing loss associated variants (Sloan-Heggen et al., 2016; De Moraes et al., 2016; Kinglu et al., 2020; Baldyga et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26752218, 36833263, 22995429, 26969326, 33152970) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 282 of the SLC26A4 protein (p.Cys282Tyr). This variant is present in population databases (rs111033454, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of SLC26A4-related conditions (PMID: 26969326, 33152970; Invitae). 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: 43568). 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 80%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 26752218). For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jan 24, 2023	The c.845G>A (NM_000441.2) variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 282 (p.Cys282Tyr). The highest population minor allele frequency in gnomAD v.2.1.1 is 0.000053 (6/113490 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.0007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.719 which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least 4 individuals with hearing loss. Of those individuals, three were compound heterozygous for the variant and a pathogenic variant observed in trans and one had a rare VUS variant on other allele (c.1001+1G>A, c.233A > G, 3.25 PM3 points, PMID:26969326,33152970, SCV000060163.6, SCV000343642.4) (PM3_Strong). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype highly specific for Pendred syndrome (PP4, PMID:26969326,33152970, SCV000060163.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, PS3_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2020	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2022

The p.Cys282Tyr variant in SLC26A4 has been identified in 5 individuals with hearing loss, two of which had EVA and carried a second, pathogenic SLC26A4 variant (Sloan-Heggen 2016 PMID: 26969326, De Moraes 2016 PMID: 26752218, Kinoglu 2020 PMID: 33152970, LMM data). It has also been identified in 0.004% (3/68020) of European chromosomes by gnomAD, v. 3 (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant was classified as Likely Pathogenic on Feb 19, 2020 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 43568). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant reduces function of the pendrin protein, however retains transport activity (de Moraes 2016 PMID: 26752218); however, these types of assays may not accurately represent biological function. In summary, due to its identification in combination with a reported pathogenic variant in an individual with hearing loss and EVA, the p.Cys282Tyr variant is likely pathogenic; however, additional studies are required to fully establish its clinical significance. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_Strong, PP3, PM2_P, PS3_Supporting. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

0.99

D;D

Vest4

0.91

MVP

0.91

MPC

0.073

ClinPred

0.89

GERP RS

5.3

Varity_R

0.67

gMVP

0.95

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