rs111033305

chr7-107690200-G-Achr7-107690200-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1226G>A(p.Arg409His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,611,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. R409C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 8.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr7-107690199-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 7-107690200-G-A is Pathogenic according to our data. Variant chr7-107690200-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107690200-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1226G>A	p.Arg409His	missense_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1226G>A	p.Arg409His	missense_variant	10/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000997 AC: 25 AN: 250826 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000815 AC: 119 AN: 1459870 Hom.: 0 Cov.: 30 AF XY: 0.0000799 AC XY: 58 AN XY: 726354

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000874

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000749 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	research	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	-	in homozygosis in two siblings with bilateralnon-syndromic sensorineural prelingual hearing loss (familial) -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2023	Variant summary: SLC26A4 c.1226G>A (p.Arg409His) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250826 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0001 vs 0.0035), allowing no conclusion about variant significance. c.1226G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Pendred Syndrome and individuals with bilateral non-syndromic hearing loss, both with and without enlarged vestibular aqueduct (e.g. Fugazzola_2007, Chai_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23918157, 17766716). Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 14, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	May 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	NM_000441.1(SLC26A4):c.1226G>A(R409H) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 17718863, 17443271, 15355436, 18813951, 11919333, 19786220, 16053392, 21961810, 24224479 and 19017801. Classification of NM_000441.1(SLC26A4):c.1226G>A(R409H) 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6 Other: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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Apr 09, 2018	A heterozygous missense variant, NM_000441.1(SLC26A4):c.1226G>A, has been identified in exon 10 of 21 of the SLC26A4 gene. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 409 of the protein (NP_000432.1(SLC26A4):p.(Arg409His)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the sulfate permease superfamily. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.009% (0 homozygotes). The variant has been previously described as pathogenic multiple times (Kahrizi K. et al. (2009), Blons H. et al. (2004); Bogazzi F. et al. (2014), Chai Y. et al. (2013)). It has also been shown to segregate with the disease in at least 1 family (Fugazzola L. et al. 2007). Additionally, it has been shown that the mutation impairs pendrin (an anion exhange protein) function. Functional studies demonstrate that mutants lose the ability to mediate iodide efflux (Gillaim M. et al. 2005). Three different variants in the same codon resulting in a change to cysteine, proline and leucine have also been shown to cause Pendred syndrome and enlarged vestibular aqueduct (ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	Jul 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	Published functional studies demonstrate a damaging effect due to reduction of pendrin-induced iodide and chloride transport (Gillam et al., 2005; Pera et al., 2008; Wasano et al., 2020); 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: 27247933, 21154317, 19017801, 16053392, 24348793, 23273637, 26226137, 22717225, 19608655, 25266519, 19786220, 9618166, 11919333, 27771369, 28964290, 30760291, 31599023, 21961810, 16570074, 24224479, 26100058, 20597900, 31541171, 31827275, 30896630, 32425884, 30275481, 31589614, 32447495, 32860223) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 409 of the SLC26A4 protein (p.Arg409His). This variant is present in population databases (rs111033305, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness or Pendred syndrome (PMID: 11919333, 16053392, 19786220, 20597900, 21961810, 24224479, 26100058, 26226137). 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: 43496). 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: 16053392). This variant disrupts the p.Arg409 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18167283, 23185506, 25372295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 02, 2017

- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Ear malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2015

The p.Arg409His variant in SLC26A4 has been identified in >20 individuals with h earing loss and EVA and/or goiter who were homozygous or compound heterozygous w ith a disease-causing variant on the remaining allele. In addition, the p.Arg40 9His variant segregated with disease in at least three affected siblings (Blons 2004, Chai 2013, Fugazzola 2007, Pera 2008, Pera 2008, Rendtorff 2013, Van Hauwe 1998, LMM data). This variant has been identified in 13/66658 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033305); however, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 hearing loss or Pendred syndrome in an autos omal recessive manner based on multiple co-occurrences with pathogenic SLC26A4 v ariants in individuals with hearing loss. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.99
MVP		1.0
MPC		0.076
ClinPred		0.66	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs111033305; hg19: chr7-107330645; COSMIC: COSV55915362; COSMIC: COSV55915362;