ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr)
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.2T>C (p.Met1Thr)
Variation ID: 43553 Accession: VCV000043553.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107661643 (GRCh38) [ NCBI UCSC ] 7: 107302088 (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 Apr 9, 2018 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Met1Thr missense initiator codon variant NR_028137.1:n.156A>G non-coding transcript variant NC_000007.14:g.107661643T>C NC_000007.13:g.107302088T>C NG_008489.1:g.6009T>C - Protein change
- M1T
- Other names
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- Canonical SPDI
- NC_000007.14:107661642:T:C
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
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
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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
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 | |
SLC26A4-AS1 | - | - | - | GRCh38 | - | 104 |
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
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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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Nov 22, 2017 | RCV000036489.7 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000797012.17 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2023 | RCV001273161.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2023 | RCV001329893.4 | |
SLC26A4-related disorder
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2023 | RCV003114215.6 |
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
(Oct 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481210.3 First in ClinVar: Feb 28, 2021 Last updated: Sep 03, 2023 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 14679580, 19204907, 21961810, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 14679580, 19204907, 21961810, 24224479] (less)
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Pathogenic
(Jan 03, 2020)
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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:
unknown
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Baylor Genetics
Accession: SCV001521449.2
First in ClinVar: Mar 22, 2021 Last updated: Sep 03, 2023 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Oct 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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SLC26A4-related disorder
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799022.3
First in ClinVar: Feb 13, 2023 Last updated: Sep 03, 2023 |
Comment:
PVS1_Strong, PS3, PM3_Strong
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Pathogenic
(Jan 06, 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: SCV003800763.1
First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023 |
Comment:
Variant summary: SLC26A4 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: SLC26A4 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 172798 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6.9e-05 vs 0.0035), allowing no conclusion about variant significance. c.2T>C has been reported in the literature in individuals affected with Enlargement of the Vestibular aqueduct and Hearing loss, usually associated with Pendred Syndrome( Example: Alber_2006, Choi_2009, Siem_2010, Sloan-Heggen_2016, Smits_2022, Gardner_2006 etc). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Choi_2009) indicating the protein was retained within the endoplasmic reticulum with no surface expression. 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 21, 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:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004024517.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
This SLC26A4 variant (rs111033302) is rare (<0.1%) in a large population dataset (gnomAD: 16/204190 total alleles; MAF 0.008%; no homozygotes) and has been reported in … (more)
This SLC26A4 variant (rs111033302) is rare (<0.1%) in a large population dataset (gnomAD: 16/204190 total alleles; MAF 0.008%; no homozygotes) and has been reported in ClinVar. This variant alters the initiation codon and is predicted to result either in absence of the protein or alteration of the encoded protein due to translation initiation at a downstream methionine codon. In vitro functional studies of p.Met1Thr using transfected cells showed the protein was retained within the endoplasmic reticulum with no surface expression. This SLC26A4 variant has been reported in unrelated individuals with hearing loss and EVA, usually in a compound heterozygous state with a different pathogenic variant. We consider c.2T>C (p.Met1Thr) to be pathogenic for DFNB4. (less)
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Pathogenic
(Nov 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060144.7
First in ClinVar: May 03, 2013 Last updated: Sep 03, 2023 |
Comment:
The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound … (more)
The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound heterozygous (Shears 20 04, Gardner 2006, Dai 2009, Choi 2009, Huang 2011, Ladsous 2014, LMM data). It h as been identified in 0.01% (14/87438) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033302). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss . This variant affects the translation initiation start codon (ATG) and is there fore predicted to disrupt translation. In vitro functional studies provide some evidence that the c.2T>C variant may impact protein function (Choi 2009). Additi onally, a different variant in the translation initiation start codon (c.3G>C) h as also been reported in an individual with hearing loss and EVA, supporting tha t changes to this codon are not tolerated. In summary, this variant meets crite ria to be classified as pathogenic for hearing loss in an autosomal recessive ma nner based on the predicted impact of the variant and multiple occurrences with pathogenic SLC26A4 variants in individuals with hearing loss. ACMG/AMP Criteria applied: PVS1; PM3_VeryStrong; PP4. (less)
Number of individuals with the variant: 3
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Pathogenic
(Mar 30, 2021)
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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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Neurogenetic Laboratory, Second Faculty of Medicine, Charles University
Accession: SCV001571601.2
First in ClinVar: Apr 24, 2021 Last updated: Sep 03, 2023 |
Clinical Features:
Hearing impairment (present)
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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: SCV002027595.2
First in ClinVar: Nov 29, 2021 Last updated: Sep 03, 2023 |
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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: SCV002027606.2
First in ClinVar: Nov 29, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(Aug 31, 2023)
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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: SCV001873704.3
First in ClinVar: Sep 19, 2021 Last updated: Sep 03, 2023 |
Comment:
Published functional studies demonstrate that variant results in protein retention in the endoplasmic reticulum (Choi et al., 2009); This variant is associated with the following … (more)
Published functional studies demonstrate that variant results in protein retention in the endoplasmic reticulum (Choi et al., 2009); This variant is associated with the following publications: (PMID: 27997596, 25372295, 19509082, 20128824, 15099345, 14679580, 24224479, 28780564, 21961810, 16950989, 23965030, 21704276, 19204907, 31589614, 34062854) (less)
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Pathogenic
(Jan 19, 2023)
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criteria provided, single submitter
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: SCV004117269.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SLC26A4 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in individuals with autosomal recessive Pendred … (more)
The SLC26A4 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in individuals with autosomal recessive Pendred syndrome or nonsyndromic enlarged vestibular aqueduct (NSEVA) (reported as "M1T" in Prasad et al. 2004. PubMed ID: 14679580; Choi et al. 2009. PubMed ID: 19204907; Ladsous et al. 2014. PubMed ID: 24224479). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107302088-T-C). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/43553). Given all the evidence, we interpret c.2T>C (p.Met1?) as pathogenic. (less)
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Pathogenic
(Jun 07, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002020679.4
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 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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Invitae
Accession: SCV000936550.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in … (more)
This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs111033302, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with nonsyndromic sensorineural hearing loss and enlargement of vestibular aqueduct (PMID: 19204907, 19509082, 21961810, 23965030, 25372295, 27997596). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43553). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SLC26A4 function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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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: SCV001455790.2
First in ClinVar: Jan 02, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955244.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965580.2 First in ClinVar: Oct 07, 2021 Last updated: Sep 03, 2023 |
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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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Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant. | Smits JJ | Human genetics | 2022 | PMID: 34410491 |
A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing. | Liu Y | PloS one | 2016 | PMID: 27997596 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
KCNJ10 may not be a contributor to nonsyndromic enlargement of vestibular aqueduct (NSEVA) in Chinese subjects. | Zhao J | PloS one | 2014 | PMID: 25372295 |
Analysis of the thyroid phenotype in 42 patients with Pendred syndrome and nonsyndromic enlargement of the vestibular aqueduct. | Ladsous M | Thyroid : official journal of the American Thyroid Association | 2014 | PMID: 24224479 |
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 |
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 |
Causes of hearing impairment in the Norwegian paediatric cochlear implant program. | Siem G | International journal of audiology | 2010 | PMID: 20553101 |
Segregation of enlarged vestibular aqueducts in families with non-diagnostic SLC26A4 genotypes. | Choi BY | Journal of medical genetics | 2009 | PMID: 19578036 |
Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss. | Dai P | Physiological genomics | 2009 | PMID: 19509082 |
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 |
Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations. | Banghova K | European journal of pediatrics | 2008 | PMID: 17876604 |
Simultaneous multigene mutation detection in patients with sensorineural hearing loss through a novel diagnostic microarray: a new approach for newborn screening follow-up. | Gardner P | Pediatrics | 2006 | PMID: 16950989 |
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 |
Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness. | Shears D | Clinical genetics | 2004 | PMID: 15099345 |
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 |
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Text-mined citations for rs111033302 ...
HelpRecord last updated Jun 02, 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.