rs111033254

Positions:

chr7-107698085-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.1588T>C(p.Tyr530His) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,609,164 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y530S) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

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 18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) 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 chr7-107698086-A-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-107698085-T-C is Pathogenic according to our data. Variant chr7-107698085-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107698085-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.1588T>C	p.Tyr530His	missense_variant	14/21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 link	c.1588T>C	p.Tyr530His	missense_variant	14/21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000477350.5 link	n.435T>C		non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5 link	n.437T>C		non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1 link	n.298T>C		non_coding_transcript_exon_variant	4/10			ENSP00000494344.1	A0A2R8Y4W7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

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:

0.0000199

AC:

AN:

251182

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135754

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1456946

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

725130

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:

0.0000424

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2022	Variant summary: SLC26A4 c.1588T>C (p.Tyr530His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251182 control chromosomes. c.1588T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Pendred syndrome (example, Coyle_1998, Borck_2003, Albert_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an effect on protein trafficking due to retention in the endoplasmic reticulum (ER) (Choi_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.1588T>C (p.Tyr530His) missense variant in the SLC26A4 gene has been reported as a common deleterious variant associated with Pendred Syndrome (Coyle et al., 1998; Blons et al., 2004). This variant has been reported in several affected individuals, often in trans with a second deleterious variant (V138F, T410M, c.2089+1G>A, V422D, T416P, Y78C, F355S) (Blons et al., 2004; Banghova et al., 2008; Borck et al., 2009; Ladsous et al., 2014). Functional studies have shown this variant affects protein localization within the cell; additionally, some affected individuals harboring this variant have elevated thyroglobulin (Choi et al., 2009; Ladsous et al., 2014). This variant is reported at low frequency within the control population databases (Exome Sequencing Project [ESP] = NA; 1000 Genomes = NA; and ExAC = 0.002). Multiple in silico algorithms predict the variant to have a deleterious effect (GERP = 5.96; CADD = 26.2; PolyPhen = 1; SIFT = 0.02). In addition, reputable diagnostic laboratories have reported this variant as Pathogenic.Therefore, this collective evidence supports the classification of the c.1588T>C (p.Tyr530His) as an autosomal recessive Pathogenic variant for Pendred Syndrome/ Non-syndromic Hearing Loss DFNB4. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 21, 2015	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 16570074, 26683941, 26485571, 17876604, 33199029, 27861301, 19204907, 19040761, 24224479, 12788906, 9618167, 26969326, 15689455, 11317356, 36147510, 14679580, 15355436) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 530 of the SLC26A4 protein (p.Tyr530His). This variant is present in population databases (rs111033254, gnomAD 0.004%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 9618167, 12788906, 19204907, 24224479, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4836). 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). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 26, 2015

The p.Tyr530His variant in SLC26A4 has been reported in at least 20 individuals with hearing loss with EVA and/or Mondini dysplasia or with Pendred syndrome (Al bert 2006, Banghova 2008, Blons 2004, Borck 2003, Campbell 2001, Choi 2009, Coyl e 1998, Prasad 2004, Pryor 2005, LMM unpublished data). The variant was compound heterozygous in at least 14 of those probands. This variant was present in 1/6 6632 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs111033254). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a r ecessive carrier frequency. One study has shown that the Tyr530His variant impa cts protein function (Choi 2009). In summary, this variant meets our criteria to be classified as pathogenic (http://personalizedmedicine.partners.org/). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.024

D;.

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.91

Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);

MVP

0.99

MPC

0.075

ClinPred

0.98

GERP RS

6.0

Varity_R

0.88

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