chr7-107674970-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 9.43
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 rank MANE Protein UniProt
SLC26A4NM_000441.2 linkc.626G>T p.Gly209Val missense_variant Exon 6 of 21 ENST00000644269.2 NP_000432.1 O43511-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkc.626G>T p.Gly209Val missense_variant Exon 6 of 21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
AF:
0.000362
AC:
55
AN:
152052
Hom.:
0
Cov.:
30
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pendred syndrome Pathogenic:6
Dec 20, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 14, 2020
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 05, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 06, 2022
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3, PM3_Strong, PP3 -

Dec 08, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6
Sep 05, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 20, 2023
Duke University Health System Sequencing Clinic, Duke University Health System
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Feb 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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). -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 14, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC26A4: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting -

Oct 02, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 04, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

SLC26A4-related disorder Pathogenic:2
Jun 04, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SLC26A4 c.626G>T variant is predicted to result in the amino acid substitution p.Gly209Val. This variant has been reported to be causative for Pendred syndrome (Van Hauwe et al. 1998. PubMed ID: 9618166; Ladsous et al. 2014. PubMed ID: 24224479; Albert et al. 2006. PubMed ID: 16570074; Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Oct 23, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Rare genetic deafness Pathogenic:1
May 11, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Mar 06, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
LIST_S2
Pathogenic
0.97
.;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111033303; hg19: chr7-107315415; API