rs111033303

chr7-107674970-G-T

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.626G>T(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,932 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. G209E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 9.43

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr7-107674970-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2735064.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 7-107674970-G-T is Pathogenic according to our data. Variant chr7-107674970-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107674970-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.626G>T	p.Gly209Val	missense_variant	6/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.626G>T	p.Gly209Val	missense_variant	6/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152052 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000966

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000302 AC: 76 AN: 251470 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

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: 0.000607

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000760 AC: 1111 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000727 AC XY: 529 AN XY: 727244

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000941

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000362 AC: 55 AN: 152052 Hom.: 0 Cov.: 30 AF XY: 0.000283 AC XY: 21 AN XY: 74288

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000554 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000709

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000441.1(SLC26A4):c.626G>T(G209V) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: 11932316, 24224479, 15689455, 19509082, 17503324, 9618166, 16570074, 16283880, 18285825 and 10190331. Classification of NM_000441.1(SLC26A4):c.626G>T(G209V) 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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 06, 2022	PS3, PM3_Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2023	Variant summary: SLC26A4 c.626G>T (p.Gly209Val) 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 0.0003 in 251470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.626G>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pendred Syndrome and non-syndromic deafness (e.g., Campbell_2001, Hutchin_2005). 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: 11317356, 16283880). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 14, 2020	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
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	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The SLC26A4 c.626G>T (p.G209V) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss. This variant is predicted to change an amino acid that is well-conserved across species (PMID: 10190331; 9618166; 11317356; 11932316; 16570074; 24224479; 26969326; 18285825; 15689455; 15355436). -
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 glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (85 heterozygotes, 0 homozygotes). (SP) 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 family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over 10 unrelated individuals with SLC26A4 -related conditions in both compound heterozygous and homozygous states (ClinVar, LOVD, PMIDs:11317356, 16570074, 19017801, 19204907, 24224479). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 209 of the SLC26A4 protein (p.Gly209Val). This variant is present in population databases (rs111033303, gnomAD 0.06%). This missense change has been observed in individuals with Pendred syndrome or deafness (PMID: 9618166, 11317356, 11932316, 16570074, 19204907, 19509082, 21366435, 24224479, 25394566, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4821). 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: 11932316). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	Published functional studies demonstrate a damaging effect on iodide transport (Taylor et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed multiple times with a different pathogenic variant in unrelated patients with features of Pendred syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Campbell et al., 2001; Blons et al., 2004; Albert et al., 2006; Choi et al., 2009; Ladsous et al., 2014; Soh et al., 2015; Cengiz et al., 2017; Roman et al., 2020); This variant is associated with the following publications: (PMID: 31971949, 31589614, 31980526, 24224479, 14679580, 11932316, 10190331, 10700480, 15355436, 19204907, 10861298, 25741868, 27771369, 25394566, 28964290, 18285825, 11317356, 9618166, 19509082, 16570074, 15689455, 16283880, 32853555, 26969326, 20301640) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SLC26A4: PM3:Very Strong, PM2:Supporting, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 11, 2017

The p.Gly209Val variant in SLC26A4 has been reported in at least 15 individuals with hearing loss and EVA (DFNB4) or Pendred syndrome (Van Hauwe 1998, Usami 199 9, Campbell 2001, Pryor 2005, Albert 2006, Pera 2008, LMM data). Many affected i ndividuals were homozygous or compound heterozygous. This variant has been ident ified in 75/126676 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs111033303); however, its frequency is low enough to be consistent with a recessive carrier frequency for Pendred s yndrome or nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4 or Pendred syndrome b ased on the previously reported biallelic occurrence in multiple affected indivi duals, association with specific clinical features, and a low frequency in the g eneral population. ACMG/AMP Criteria applied: PM3_Strong, PS4, PP4. -

SLC26A4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 23, 2018

The SLC26A4 c.626G>T (p.Gly209Val) missense variant has been reported in at least eight studies in related and unrelated probands, including one in a homozygous state and 17 in a compound heterozygous state (Van Hauwe et al. 1998; Campbell et al. 2001; Taylor et al. 2002; Pryor et al. 2005; Pera et al. 2008; Ladsous et al. 2014; Soh et al. 2015; Sloan-Heggen et al. 2016). Pera et al. (2008) described two affected siblings who were compound heterozygous for the p.Gly209Val variant and another variant, while their unaffected parents were identified as carriers. The p.Gly209Val variant was absent from 314 controls, but is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. In HeLa cells, the p.Gly209Val variant showed normal cellular localization, but reduced iodide efflux compared to wildtype (Taylor et al. 2002). Based on the collective evidence, this variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.9	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		1.0
MVP		0.99
MPC		0.075
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033303; hg19: chr7-107315415;