ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.-3-2A>G
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.-3-2A>G
Variation ID: 43486 Accession: VCV000043486.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107661637 (GRCh38) [ NCBI UCSC ] 7: 107302082 (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 Oct 8, 2024 Mar 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2:c.-3-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NR_028137.1:n.162T>C non-coding transcript variant NC_000007.14:g.107661637A>G NC_000007.13:g.107302082A>G NG_008489.1:g.6003A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:107661636:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00019
Exome Aggregation Consortium (ExAC) 0.00022
The Genome Aggregation Database (gnomAD) 0.00027
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
1376 | 1574 | |
SLC26A4-AS1 | - | - | - | GRCh38 | - | 104 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
criteria provided, single submitter
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May 9, 2022 | RCV000036415.7 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000665503.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2018 | RCV000824761.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV001063867.24 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 21, 2024 | RCV001785456.5 | |
SLC26A4-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Dec 4, 2023 | RCV004534761.2 |
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
(May 09, 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: SCV000894401.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060070.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The c.-3-2A>G variant in SLC26A4 has been identified in 11 compound heterozygous individuals and 1 homozygous individual with hearing loss and clinical features of DFNB4-related … (more)
The c.-3-2A>G variant in SLC26A4 has been identified in 11 compound heterozygous individuals and 1 homozygous individual with hearing loss and clinical features of DFNB4-related hearing loss/Pendred syndrome (EVA or temporal bone abnormalit ies and one with a goiter) (Lopez-Bigas 2001, Pryor 2005, Albert 2006, Choi 2009 a, Choi 2009b, Soh 2015, DeLuca 2015, LMM data). This variant has also been iden tified in 21/88534 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with a recess ive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for DFNB4-related hearing loss/Pendred syndrome in an autosomal recessive manner based upon presence in affected individuals and predi cted impact on protein. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS4, PM 2_Supporting (less)
Number of individuals with the variant: 18
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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: SCV002027573.1
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: SCV002027584.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Dec 20, 2021)
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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: SCV001787543.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 19204907, 25525159, 21704276, 23965030, 15689455, 14679580, 16570074, 25394566, 26022370) (less)
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Pathogenic
(Jan 29, 2024)
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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: SCV001228731.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 1 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. … (more)
This sequence change falls in intron 1 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs397516411, gnomAD 0.02%). This variant has been observed in individuals with SLC26A4-related conditions (PMID: 16570074, 25394566, 26022370). This variant is also known as IVS1-2A>G or IVS1-3-2A>G. ClinVar contains an entry for this variant (Variation ID: 43486). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 21, 2024)
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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: SCV004201817.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jan 03, 2020)
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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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Myriad Genetics, Inc.
Accession: SCV001193899.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000441.1(SLC26A4):c.-3-2A>G is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID: 25394566, 21704276, 23965030 and 16570074. … (more)
NM_000441.1(SLC26A4):c.-3-2A>G is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID: 25394566, 21704276, 23965030 and 16570074. Classification of NM_000441.1(SLC26A4):c.-3-2A>G is based on the following criteria: This variant 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. (less)
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Pathogenic
(Dec 02, 2022)
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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: SCV002819509.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: SLC26A4 c.-3-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SLC26A4 c.-3-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 168934 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.-3-2A>G has been reported in the literature in individuals affected with Pendred Syndrome or hearing loss (Rodriguez-Paris_2010, Sloan-Heggen_2016, Yoon_2020), and these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557931.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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, autosomal recessive 4, with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (39 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is moderately conserved. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic in both compound heterozygous and homozygous individuals (ClinVar, deafnessvariationdatabase). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002586186.14
First in ClinVar: Oct 22, 2022 Last updated: Oct 08, 2024 |
Comment:
SLC26A4: PM3:Very Strong, PVS1:Strong, PM2
Number of individuals with the variant: 1
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Pathogenic
(Dec 04, 2023)
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no assertion criteria provided
Method: clinical testing
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SLC26A4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004731138.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SLC26A4 c.-3-2A>G variant is located in the 5' untranslated region. This variant is predicted to disrupt the AG acceptor site and interfere with normal … (more)
The SLC26A4 c.-3-2A>G variant is located in the 5' untranslated region. This variant is predicted to disrupt the AG acceptor site and interfere with normal splicing. This variant has been reported in multiple patients as causative for autosomal recessive Pendred syndrome or nonsyndromic hearing loss with/without enlarged vestibular aqueduct (described as IVS1-3-2A>G, Albert. 2006. PubMed ID: 16570074; described as c.3-2A>G, Soh. 2015. PubMed ID: 25394566; Yoon. 2020. PubMed ID: 32658404; DeLuca. 2015. PubMed ID: 26022370). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel Variants in Hearing Loss Genes and Associations With Audiometric Thresholds in a Multi-ethnic Cohort of US Patients With Cochlear Implants. | Yoon PJ | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2020 | PMID: 32658404 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Apparent Usher Syndrome Caused by the Combination of BBS1-Associated Retinitis Pigmentosa and SLC26A4-Associated Deafness. | DeLuca AP | JAMA ophthalmology | 2015 | PMID: 26022370 |
Evaluation of genotype-phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome. | Soh LM | European journal of endocrinology | 2015 | PMID: 25394566 |
Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in Pendred syndrome/enlarged vestibular aqueducts. | Landa P | BMC medical genetics | 2013 | PMID: 23965030 |
Mutation analysis of SLC26A4 for Pendred syndrome and nonsyndromic hearing loss by high-resolution melting. | Chen N | The Journal of molecular diagnostics : JMD | 2011 | PMID: 21704276 |
Genotyping with a 198 mutation arrayed primer extension array for hereditary hearing loss: assessment of its diagnostic value for medical practice. | Rodriguez-Paris J | PloS one | 2010 | PMID: 20668687 |
Segregation of enlarged vestibular aqueducts in families with non-diagnostic SLC26A4 genotypes. | Choi BY | Journal of medical genetics | 2009 | PMID: 19578036 |
Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms? | Choi BY | Human mutation | 2009 | PMID: 19204907 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
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 |
SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. | Pryor SP | Journal of medical genetics | 2005 | PMID: 15689455 |
Pendred syndrome and DFNB4-mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of eleven novel mutations. | Prasad S | American journal of medical genetics. Part A | 2004 | PMID: 14679580 |
Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment. | López-Bigas N | Human mutation | 2001 | PMID: 11748854 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs397516411 ...
HelpRecord last updated Oct 13, 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.