ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.1174A>T (p.Asn392Tyr)
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.1174A>T (p.Asn392Tyr)
Variation ID: 446453 Accession: VCV000446453.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107690148 (GRCh38) [ NCBI UCSC ] 7: 107330593 (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 Dec 3, 2017 Feb 14, 2024 Nov 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2:c.1174A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Asn392Tyr missense NC_000007.14:g.107690148A>T NC_000007.13:g.107330593A>T NG_008489.1:g.34514A>T - Protein change
- N392Y
- Other names
- -
- Canonical SPDI
- NC_000007.14:107690147:A: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
1340 | 1535 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Feb 10, 2023 | RCV000515717.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2023 | RCV000657916.8 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 22, 2021 | RCV001835832.1 |
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 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: yes
Allele origin:
germline
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Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center
Accession: SCV000611812.1
First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hearing impairment (present)
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Pathogenic
(May 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000779683.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
The N392Y missense variant has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Huang et al., 2011; … (more)
The N392Y missense variant has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Huang et al., 2011; Luo et al., 2017; Reyes et al., 2009). Functional studies report that N392Y resulted in the change of intracellular localization of the protein and the loss of anion transporter activity (Ishihara et al., 2010). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we consider this to be a pathogenic variant. (less)
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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: SCV002026865.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Feb 10, 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: SCV004204216.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 06, 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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Invitae
Accession: SCV001224335.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 392 of the SLC26A4 protein (p.Asn392Tyr). … (more)
This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 392 of the SLC26A4 protein (p.Asn392Tyr). This variant is present in population databases (rs201562855, gnomAD 0.006%). This missense change has been observed in individual(s) with nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 17718863, 19786220, 21961810). 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: 446453). 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: 20826203). For these reasons, this variant has been classified as Pathogenic. (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: SCV000902368.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 2
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: clinical testing, in vitro
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Autosomal recessive nonsyndromic hearing loss 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited,
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: SCV000994882.2
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_normal; signal at cell membrane_negative; intracellular puncta_negative
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Pathogenic
(Jan 22, 2021)
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no assertion criteria provided
Method: clinical testing
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Pendred syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002079990.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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: SCV000994882.2
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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 |
Two Compound Heterozygous Were Identified in SLC26A4 Gene in Two Chinese Families With Enlarged Vestibular Aqueduct. | Yu Y | Clinical and experimental otorhinolaryngology | 2019 | PMID: 30086623 |
Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain. | Bassot C | Biochimie | 2017 | PMID: 27771369 |
Comparative study of mutation spectrums of MT-RNR1 m.1555A>G, GJB2, and SLC26A4 between familial and sporadic patients with nonsyndromic sensorineural hearing loss in Chinese Han. | Li Q | Chinese medical journal | 2014 | PMID: 25266519 |
Extremely discrepant mutation spectrum of SLC26A4 between Chinese patients with isolated Mondini deformity and enlarged vestibular aqueduct. | Huang S | Journal of translational medicine | 2011 | PMID: 21961810 |
[An investigation of SLC26A4 gene mutation in nonsydromic hearing impairment in Hunan province of China]. | Jiang L | Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery | 2010 | PMID: 20842945 |
Salicylate restores transport function and anion exchanger activity of missense pendrin mutations. | Ishihara K | Hearing research | 2010 | PMID: 20826203 |
Mutation analysis of SLC26A4 in mainland Chinese patients with enlarged vestibular aqueduct. | Reyes S | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2009 | PMID: 19786220 |
A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. | Wang QJ | Clinical genetics | 2007 | PMID: 17718863 |
Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness. | Park HJ | Journal of medical genetics | 2003 | PMID: 12676893 |
Text-mined citations for rs201562855 ...
HelpRecord last updated Apr 06, 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.