ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.578C>T (p.Thr193Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000441.2(SLC26A4):c.578C>T (p.Thr193Ile)
Variation ID: 4830 Accession: VCV000004830.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107674326 (GRCh38) [ NCBI UCSC ] 7: 107314771 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2015 Jun 17, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2:c.578C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Thr193Ile missense NC_000007.14:g.107674326C>T NC_000007.13:g.107314771C>T NG_008489.1:g.18692C>T O43511:p.Thr193Ile - Protein change
- T193I
- Other names
- -
- Canonical SPDI
- NC_000007.14:107674325:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC26A4 | - | - |
GRCh38 GRCh37 |
1374 | 1572 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2023 | RCV000005101.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV000036499.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV000824763.7 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000770869.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV001389159.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015120.2
First in ClinVar: Nov 20, 2021 Last updated: Aug 26, 2023 |
Comment:
Variant summary: SLC26A4 c.578C>T (p.Thr193Ile) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five … (more)
Variant summary: SLC26A4 c.578C>T (p.Thr193Ile) 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 2e-05 in 251446 control chromosomes (gnomAD). c.578C>T has been reported in the literature in multiple individuals affected with Pendred Syndrome/Non-Syndromic Hearing Loss, including a family in which the variant was shown to segregate with disease (e.g. Adato_2000, Albert_2006, Tang_2015). Functional studies have shown the variant was undetectable in the plasma membrane, completely retained in the endoplasmic reticulum and showed no transport function (Moraes_2015, Wasano_2020). The following publications have been ascertained in the context of this evaluation (PMID: 10878664, 26752218, 25991456, 31599023, 16570074). Seven submitters have cited 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. (less)
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Pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060154.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Thr193Ile variant in SLC26A4 has been reported in at least 5 individuals with nonsyndromic hearing loss and enlarged vestibular aqueduct or Pendred syndrome in … (more)
The p.Thr193Ile variant in SLC26A4 has been reported in at least 5 individuals with nonsyndromic hearing loss and enlarged vestibular aqueduct or Pendred syndrome in the homozygous or compound heterozygous state, and segregated with hearing loss in affected family members (Adato 2000 PMID: 1087866, Cengiz 2017 PMID: 28964290, Albert 2006 PMID: 16570074, Blons 2004 PMID: 15355436). It has also been identified in 0.001% (1/68018) 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 has also been reported in ClinVar (Variation ID 4830). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies suggest the variant impairs protein localization and function (De Moraes PMID: 26752218, Wasano 2020 PMID: 31599023). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred Syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong,, PM2_Supporting, PP1, PP3, PS3_Supporting. (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201875.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Apr 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000799426.1
First in ClinVar: Oct 07, 2016 Last updated: Oct 07, 2016 |
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Likely pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002026598.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002026609.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894402.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001590425.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 193 of the SLC26A4 protein (p.Thr193Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 193 of the SLC26A4 protein (p.Thr193Ile). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 26752218, 31599023). 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. ClinVar contains an entry for this variant (Variation ID: 4830). This variant is also known as 801C>T. This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 10878664, 20597900, 26752218, 28964290). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111033348, gnomAD 0.003%). (less)
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Pathogenic
(Jun 01, 2000)
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no assertion criteria provided
Method: literature only
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PENDRED SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025277.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 07, 2016 |
Comment on evidence:
In a Druze family, Adato et al. (2000) found a C-to-T transition at nucleotide 801 in exon 5 of the SLC26A4 gene, predicted to result … (more)
In a Druze family, Adato et al. (2000) found a C-to-T transition at nucleotide 801 in exon 5 of the SLC26A4 gene, predicted to result in a thr193-to-ile amino acid substitution in the protein. Members of this family were first diagnosed with recessive nonsyndromic hearing loss (Baldwin et al., 1995), i.e., DFNB4 (see 600791). Subsequent tests showed that they had goiter and therefore the diagnosis was changed to Pendred syndrome (PDS; 274600). (less)
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Likely pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902381.1
First in ClinVar: May 12, 2019 Last updated: May 12, 2019 |
Number of individuals with the variant: 1
Clinical Features:
hearing loss (present)
Family history: yes
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Affects
(Aug 20, 2019)
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no assertion criteria provided
Method: literature only, in vitro
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Autosomal recessive nonsyndromic hearing loss 4
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
germline
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National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center
Additional submitter:
The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University
Accession: SCV000994872.2
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
in vitro experiment
Observation 1: Observation 2:
Result:
HCO3-/Cl- exchange_impaired; I-/Cl- exchange_impaired; signal at cell membrane_negative; intracellular puncta_negative
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center
Additional submitter:
The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University
Accession: SCV000994872.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Systematic quantification of the anion transport function of pendrin (SLC26A4) and its disease-associated variants. | Wasano K | Human mutation | 2020 | PMID: 31599023 |
Novel pathogenic variants underlie SLC26A4-related hearing loss in a multiethnic cohort. | Cengiz FB | International journal of pediatric otorhinolaryngology | 2017 | PMID: 28964290 |
Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain. | Bassot C | Biochimie | 2017 | PMID: 27771369 |
Reduction of Cellular Expression Levels Is a Common Feature of Functionally Affected Pendrin (SLC26A4) Protein Variants. | de Moraes VCS | Molecular medicine (Cambridge, Mass.) | 2016 | PMID: 26752218 |
DNA sequence analysis and genotype-phenotype assessment in 71 patients with syndromic hearing loss or auditory neuropathy. | Tang HY | BMJ open | 2015 | PMID: 25991456 |
Molecular analysis of SLC26A4 gene in patients with nonsyndromic hearing loss and EVA: identification of two novel mutations in Brazilian patients. | de Moraes VC | International journal of pediatric otorhinolaryngology | 2013 | PMID: 23273637 |
Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without Enlarged Vestibular Aqueduct (EVA). | Pourová R | Annals of human genetics | 2010 | PMID: 20597900 |
Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies. | Palos F | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 17940114 |
SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. | Albert S | European journal of human genetics : EJHG | 2006 | PMID: 16570074 |
Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity. | Blons H | Clinical genetics | 2004 | PMID: 15355436 |
Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus. | Adato A | European journal of human genetics : EJHG | 2000 | PMID: 10878664 |
Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. | Baldwin CT | Human molecular genetics | 1995 | PMID: 8541853 |
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Text-mined citations for rs111033348 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.