ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.2168A>G (p.His723Arg)
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
-
NM_000441.2(SLC26A4):c.2168A>G (p.His723Arg)
Variation ID: 4825 Accession: VCV000004825.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107710132 (GRCh38) [ NCBI UCSC ] 7: 107350577 (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 Oct 1, 2013 Apr 20, 2024 Jan 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000441.2:c.2168A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.His723Arg missense NC_000007.14:g.107710132A>G NC_000007.13:g.107350577A>G NG_008489.1:g.54498A>G O43511:p.His723Arg - Protein change
- H723R
- Other names
- -
- Canonical SPDI
- NC_000007.14:107710131:A:G
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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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0.00040 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00012
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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
Help
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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LOC123956210 | - | - | - | GRCh38 | - | 73 |
SLC26A4 | - | - |
GRCh38 GRCh37 |
1335 | 1530 |
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 (7) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000005094.13 | |
Pathogenic/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2022 | RCV000005095.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2019 | RCV000036477.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV000480319.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000778813.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2021 | RCV002476929.1 |
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
(Aug 20, 2019)
|
criteria provided, single submitter
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: SCV000994909.2
First in ClinVar: Mar 01, 2020 Last updated: May 04, 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_positive; splicing_unaffected
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Pathogenic
(Jan 19, 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: SCV002074332.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: SLC26A4 c.2168A>G (p.His723Arg) results in a non-conservative amino acid change located in the STAS domain of the encoded protein sequence. Five of five … (more)
Variant summary: SLC26A4 c.2168A>G (p.His723Arg) results in a non-conservative amino acid change located in the STAS domain 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 0.00012 in 251294 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.2168A>G has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss (e.g. Sagong_2012, Jung_2016). These data indicate that the variant is very likely to be associated with disease. Fifteen 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
(Aug 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060132.7
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.His723Arg variant in SLC26A4 has been reported in 37 probands with Pendred syndrome (Wu 2005, Van Hauwe 1998, Lee 2008, Asakura 2010, Cho 2006, … (more)
The p.His723Arg variant in SLC26A4 has been reported in 37 probands with Pendred syndrome (Wu 2005, Van Hauwe 1998, Lee 2008, Asakura 2010, Cho 2006, Dai 2008, Hu 2007, Ishihara 2010, Kim 2009, Park 2003, Reyes 2009, Tsukamoto 2003, Usami 1999, Yoon 2008). Many of these probands were homozygous or compound heterozygous, and the variant has segregated with disease in several families. Furthermore, functional studies revealed that the p.His723Arg variant disrupts the normal cellular localization and ion transport activity of the protein (Yoon 2008, Ishihara 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate. (less)
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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Pendred syndrome
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267506.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 2
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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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
|
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center
Accession: SCV000611824.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 22
Clinical Features:
Hearing impairment (present)
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Pathogenic
(Sep 22, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000886131.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, … (more)
The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, 1998; Ishihara, 2010; Sagong, 2013; Asakura, 2010; Li, 2016). Lee (2014) noted that patients with two copies of the p.His723Arg variant had poorer hearing and higher proportion of incomplete cochlear turns (Mondini structures) compared to compound heterozygotes with a single copy and a different SLC26A4 variant. Cell-based and biochemical experiments further demonstrated that p.His723Arg polypeptides are impaired at reaching the plasma membrane and exhibit abnormal ion exchange activity that can be rescued at low temperature (Yoon, 2008). This variant is listed in the Genome Aggregation Database (gnomAD) in the East Asian population at a frequency of 0.16 percent (identified on 31 out of 18,868 chromosomes with 0 homozygotes) and is reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 4825). The histidine at position 723 is highly conserved across 12 species (Alamut v2.9.0), and computational analyses of the effects of the p.His723Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether the p.His723Arg variant is pathogenic. (less)
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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SLC26A4-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915193.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection … (more)
The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg 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. (less)
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163099.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Dec 04, 2019)
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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: SCV001194173.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000441.1(SLC26A4):c.2168A>G(H723R) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18310264, 24007330, 20826203 and 17718863. Classification … (more)
NM_000441.1(SLC26A4):c.2168A>G(H723R) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18310264, 24007330, 20826203 and 17718863. Classification of NM_000441.1(SLC26A4):c.2168A>G(H723R) 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. (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: SCV002026974.1
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: SCV002026975.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
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Pathogenic
(Jan 03, 2022)
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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
|
3billion
Accession: SCV002058697.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004825, PMID:9618166, PS1_S).A different … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004825, PMID:9618166, PS1_S).A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000949741, PMID:19040761,24599119, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000113, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pendred syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001244768.2
First in ClinVar: May 04, 2020 Last updated: Dec 24, 2022 |
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 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 (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 32 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 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 STAS domain (DECIPHER, Uniprot). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is prevalent in individuals with Asian descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (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
(Nov 08, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Pendred syndrome
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800066.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Dec 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568753.5
First in ClinVar: Apr 27, 2017 Last updated: Jan 07, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with intracellular retention and decreased protein activity in comparison to wild type (Yoon et al., 2008); In silico … (more)
Published functional studies demonstrate a damaging effect with intracellular retention and decreased protein activity in comparison to wild type (Yoon et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20842945, 19786220, 20583162, 23705809, 25266519, 22884721, 20826203, 23469187, 23755160, 24224479, 9618166, 27176802, 28583500, 27082237, 30693673, 32477112, 31599023, 34943631, 34943614, 11405873, 24007330, 22975760, 11502831, 21961810, 24338212, 26035154, 26100058, 26346818, 27384033, 26763877, 28990112, 28981942, 28786104, 28964290, 27374754, 28802383, 29234782, 28093008, 28052261, 17322586, 30282152, 29447821, 30589569, 30036422, 30733538, 31347505, 30842343, 31564438, 29650690, 31541171, 31827275, 32203226, 30896630, 32425884, 30275481, 32877901, 34170635, 32447495, 15905611, 32459320, 32645618, 32536503, 33597575, 33724713, 34006472, 35204885, 35276235, 35114279, 34801268, 35249537, 34545167, 18310264) (less)
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Pathogenic
(May 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Pendred syndrome
(Autosomal recessive inheritance)
Affected status: yes, unknown, no
Allele origin:
maternal,
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV003935252.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Observation 1:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Tissue: blood
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Tissue: blood
Observation 3:
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Tissue: blood
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Pathogenic
(Oct 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201811.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000939369.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 723 of the SLC26A4 protein (p.His723Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 723 of the SLC26A4 protein (p.His723Arg). This variant is present in population databases (rs121908362, gnomAD 0.2%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11405873, 17322586, 20583162, 22884721, 23705809, 24338212). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4825). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 20583162). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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PENDRED SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025271.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015 |
Comment on evidence:
In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of … (more)
In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of the SLC26A4 gene, causing a his723-to-arg (H723R) substitution. This mutation was found in homozygosity in 1 family and in compound heterozygosity in affected members of the other 2 families, who also carried a 2162C-T transition in exon 19 of the SLC26A4 gene, resulting in a thr721-to-met (T721M; 605646.0012) substitution. Tekin et al. (2003) identified the H723R mutation in homozygous state in a Turkish patient with classic Pendred syndrome (PDS; 274600). They noted that the mutation had been identified in families from Japan and China in which affected members had sensorineural hearing loss and enlarged vestibular aqueduct without goiter. Tekin et al. (2003) suggested that the detection of the H723R mutation in Turkey reflected the migration of the Turkish people from central Asia more than 1,000 years ago. In 2 sibs with enlarged vestibular aqueduct and an unrelated patient with Pendred syndrome, Tsukamoto et al. (2003) identified compound heterozygosity for the H723R and T721M mutations in the SLC26A4 gene, and concluded that the 2 conditions are part of a continuous spectrum of disease. Among 26 Korean patients with DFNB4 with enlarged vestibular aqueduct (EVA), Park et al. (2005) found that the H723R mutation was the most common, accounting for 40% of the mutant alleles. Among Chinese patients with DFNB4 with EVA, Wang et al. (2007) found that H723R was the second most common mutation, accounting for 9% of mutant alleles. Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the H723R mutant protein was retained in the endoplasmic reticulum, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, but the defects could be rescued considerably by decreased temperature. (less)
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025270.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015 |
Comment on evidence:
In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of … (more)
In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of the SLC26A4 gene, causing a his723-to-arg (H723R) substitution. This mutation was found in homozygosity in 1 family and in compound heterozygosity in affected members of the other 2 families, who also carried a 2162C-T transition in exon 19 of the SLC26A4 gene, resulting in a thr721-to-met (T721M; 605646.0012) substitution. Tekin et al. (2003) identified the H723R mutation in homozygous state in a Turkish patient with classic Pendred syndrome (PDS; 274600). They noted that the mutation had been identified in families from Japan and China in which affected members had sensorineural hearing loss and enlarged vestibular aqueduct without goiter. Tekin et al. (2003) suggested that the detection of the H723R mutation in Turkey reflected the migration of the Turkish people from central Asia more than 1,000 years ago. In 2 sibs with enlarged vestibular aqueduct and an unrelated patient with Pendred syndrome, Tsukamoto et al. (2003) identified compound heterozygosity for the H723R and T721M mutations in the SLC26A4 gene, and concluded that the 2 conditions are part of a continuous spectrum of disease. Among 26 Korean patients with DFNB4 with enlarged vestibular aqueduct (EVA), Park et al. (2005) found that the H723R mutation was the most common, accounting for 40% of the mutant alleles. Among Chinese patients with DFNB4 with EVA, Wang et al. (2007) found that H723R was the second most common mutation, accounting for 9% of mutant alleles. Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the H723R mutant protein was retained in the endoplasmic reticulum, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, but the defects could be rescued considerably by decreased temperature. (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: SCV000902362.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 4
Clinical Features:
hearing loss (present)
Family history: yes
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Pathogenic
(May 12, 2020)
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no assertion criteria provided
Method: clinical testing
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Pendred syndrome
Affected status: yes
Allele origin:
inherited
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The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine
Accession: SCV001438729.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Elevated TSH levels (present) , normal T3 levels (present) , normal T4 levels (present) , Ectopic thyroid (present)
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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: SCV001459941.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Pendred syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000086786.3
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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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
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A brief description of the result of this method for this variant. |
Submitter
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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
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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: SCV000994909.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. | Li M | Nature communications | 2020 | PMID: 32165640 |
Systematic quantification of the anion transport function of pendrin (SLC26A4) and its disease-associated variants. | Wasano K | Human mutation | 2020 | PMID: 31599023 |
Pendred Syndrome / Nonsyndromic Enlarged Vestibular Aqueduct. | Adam MP | - | 2020 | PMID: 20301640 |
Vestibular function is associated with residual low-frequency hearing loss in patients with bi-allelic mutations in the SLC26A4 gene. | Jung J | Hearing research | 2016 | PMID: 26900070 |
Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis. | Lu YJ | Medicine | 2015 | PMID: 26683941 |
Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations. | Yao J | Scientific reports | 2015 | PMID: 26035154 |
Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. | Tsukada K | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25999548 |
Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study. | Miyagawa M | Journal of human genetics | 2014 | PMID: 24599119 |
Intrafamilial phenotypic variability in families with biallelic SLC26A4 mutations. | Song MH | The Laryngoscope | 2014 | PMID: 24338212 |
Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations. | Lee HJ | Clinical genetics | 2014 | PMID: 24007330 |
Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome. | Ganaha A | BMC medical genetics | 2013 | PMID: 23705809 |
Molecular epidemiology and functional assessment of novel allelic variants of SLC26A4 in non-syndromic hearing loss patients with enlarged vestibular aqueduct in China. | Yuan Y | PloS one | 2012 | PMID: 23185506 |
Salicylate restores transport function and anion exchanger activity of missense pendrin mutations. | Ishihara K | Hearing research | 2010 | PMID: 20826203 |
A patient with Pendred syndrome whose goiter progressed with normal serum thyrotropin and iodine organification. | Asakura Y | American journal of medical genetics. Part A | 2010 | PMID: 20583162 |
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 Family of H723R Mutation for SLC26A4 Associated with Enlarged Vestibular Aqueduct Syndrome. | Kim S | Clinical and experimental otorhinolaryngology | 2009 | PMID: 19565036 |
Molecular etiology of hearing impairment in Inner Mongolia: mutations in SLC26A4 gene and relevant phenotype analysis. | Dai P | Journal of translational medicine | 2008 | PMID: 19040761 |
Molecular analysis of the GJB2, GJB6 and SLC26A4 genes in Korean deafness patients. | Lee KY | International journal of pediatric otorhinolaryngology | 2008 | PMID: 18585793 |
Heterogeneity in the processing defect of SLC26A4 mutants. | Yoon JS | Journal of medical genetics | 2008 | PMID: 18310264 |
A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. | Wang QJ | Clinical genetics | 2007 | PMID: 17718863 |
Molecular analysis of hearing loss associated with enlarged vestibular aqueduct in the mainland Chinese: a unique SLC26A4 mutation spectrum. | Hu H | Journal of human genetics | 2007 | PMID: 17443271 |
The H723R mutation in the PDS/SLC26A4 gene is associated with typical Pendred syndrome in Korean patients. | Cho MA | Endocrine | 2006 | PMID: 17322586 |
Prevalent SLC26A4 mutations in patients with enlarged vestibular aqueduct and/or Mondini dysplasia: a unique spectrum of mutations in Taiwan, including a frequent founder mutation. | Wu CC | The Laryngoscope | 2005 | PMID: 15933521 |
Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans. | Park HJ | Clinical genetics | 2005 | PMID: 15679828 |
Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese. | Tsukamoto K | European journal of human genetics : EJHG | 2003 | PMID: 14508505 |
Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey. | Tekin M | Clinical genetics | 2003 | PMID: 12974744 |
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 |
Long-term audiological feature in Pendred syndrome caused by PDS mutation. | Iwasaki S | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11405873 |
Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. | Usami S | Human genetics | 1999 | PMID: 10190331 |
Two frequent missense mutations in Pendred syndrome. | Van Hauwe P | Human molecular genetics | 1998 | PMID: 9618166 |
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Text-mined citations for rs121908362 ...
HelpRecord last updated May 01, 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.