ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu)
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.1003T>C (p.Phe335Leu)
Variation ID: 4842 Accession: VCV000004842.82
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.3 7: 107689054 (GRCh38) [ NCBI UCSC ] 7: 107329499 (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 7, 2016 Apr 20, 2024 Aug 19, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000441.2(SLC26A4):c.1003T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000441.2:c.1003T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Phe335Leu missense NC_000007.14:g.107689054T>C NC_000007.13:g.107329499T>C NG_008489.1:g.33420T>C O43511:p.Phe335Leu - Protein change
- F335L
- Other names
- -
- Canonical SPDI
- NC_000007.14:107689053:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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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0.00080 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00091
The Genome Aggregation Database (gnomAD) 0.00077
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00109
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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SLC26A4 | - | - |
GRCh38 GRCh37 |
1332 | 1527 |
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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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000005114.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000036420.15 | |
Likely pathogenic (6) |
reviewed by expert panel
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Aug 19, 2020 | RCV000576732.24 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000656976.33 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2018 | RCV000779523.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 23, 2022 | RCV000824769.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 25, 2022 | RCV002291265.10 |
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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Likely pathogenic
(Aug 19, 2020)
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reviewed by expert panel
Method: curation
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Pendred syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001438398.5
First in ClinVar: Oct 23, 2020 Last updated: Nov 11, 2023 |
Comment:
The c.1003T>C (p.Phe335Leu) variant has been identified in over 20 probands with Hearing loss, 6 of whom had a second pathogenic or suspected pathogenic variant … (more)
The c.1003T>C (p.Phe335Leu) variant has been identified in over 20 probands with Hearing loss, 6 of whom had a second pathogenic or suspected pathogenic variant in trans (PM3_VeryStrong; PMIDs: 19509082, 29293505, 25394566, 20668687, 20597900, 19426954, 19204907, 18285825, 17503324, 17357124, 17309986, 15689455, 14679580, 11317356, Laboratory for Molecular Medicine internal data). The variant has been reported to segregate with disease in one affected family member (PP1; PMID: 18285825). Multiple probands presented with hearing loss and enlarged vestibular aqueducts (EVA) which are highly specific to Pendred syndrome (PP4; PMIDs: 14679580, 18285825, 19509082, 25394566, Laboratory for Molecular Medicine internal data). Evidence has been published indicating that the p.Phe335Leu variant may be pathogenic when in trans with a functionally-null or severely hypomorphic variant but not as a mono-allelic variant or in the homozygous state (PMIDs: 19204907, 24051746). The c.1003T>C (p.Phe335Leu) variant was present in 0.203% (76/30612 CI 95%) of South Asian alleles in gnomAD v2.1.1, which is a high enough frequency apply BS1_Supporting. Additionally it was present in 2.1% (27/910 CI 95%) of Amish alleles in gnomAD v3.1 (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Pendred syndrome outweighs the high allele frequency of the variant in population databases. Therefore, neither BS1_Supporting nor BA1 will contribute to the overall classification. A functional study demonstrates that the p.Phe335Leu variant may impact protein function (PS3_Supporting; PMID: 19204907). Finally, the REVEL computational prediction analysis tool produced a score of 0.828, which is above the threshold necessary to apply PP3. In summary, this variant has been classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PS3_Supporting, PP1, PP3, PP4. (less)
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Likely pathogenic
(Dec 17, 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: SCV001194145.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_000441.1(SLC26A4):c.1003T>C(F335L) is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 29372807, 25394566, 26485571, 27771369, 29293505, … (more)
NM_000441.1(SLC26A4):c.1003T>C(F335L) is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 29372807, 25394566, 26485571, 27771369, 29293505, 28444304 and 28984810. Classification of NM_000441.1(SLC26A4):c.1003T>C(F335L) 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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Likely pathogenic
(May 18, 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: SCV001652762.1
First in ClinVar: May 28, 2021 Last updated: May 28, 2021 |
Sex: mixed
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Pathogenic
(Feb 28, 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: SCV003844306.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: SLC26A4 c.1003T>C (p.Phe335Leu) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR002645) of the encoded protein sequence. Four … (more)
Variant summary: SLC26A4 c.1003T>C (p.Phe335Leu) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 251190 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00086 vs 0.0035), allowing no conclusion about variant significance. c.1003T>C has been reported in the literature in multiple individuals affected with Pendred Syndrome (Teek_2013, Rendtorff_2013, etc.) and EVA (Hearing loss and enlargement of the vestibular aqueduct) (Pera_2008, Choi_2009, Muskett_2016, etc.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating showing the variant effect results in reduced protein activity (Choi_2009). 14 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=4), likely pathogenic (n=9) including the ClinGen Hearing Loss Variant Curation Expert Panel, or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(-)
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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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Lifecell International Pvt. Ltd
Accession: SCV003842260.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Comment:
A Heterozygous Missense, Splice site region variant c.1003T>C in Exon 9 of the SLC26A4 gene that results in the amino acid substitution p.Phe335Leu was identified. … (more)
A Heterozygous Missense, Splice site region variant c.1003T>C in Exon 9 of the SLC26A4 gene that results in the amino acid substitution p.Phe335Leu was identified. The observed variant has a minor allele frequency of 0.086%, in gnomAD exomes and 0.045% in genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as LikelyPathogenic. For these reasons, this variant has been classified as Likely Pathogenic (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Likely pathogenic
(Apr 19, 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: SCV000565574.9
First in ClinVar: Apr 29, 2017 Last updated: Apr 30, 2023 |
Comment:
Published functional studies have shown normal plasma membrane localization but lower exchange rate constant for p.(F335L) compared to wild-type constructs (Choi et al., 2009); the … (more)
Published functional studies have shown normal plasma membrane localization but lower exchange rate constant for p.(F335L) compared to wild-type constructs (Choi et al., 2009); the significance of this residual activity for overall protein function is currently unclear; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV001438398.2; Oza et al., 2018); This variant is associated with the following publications: (PMID: 20668687, 21704276, 36499699, 19426954, 27771369, 23965030, 14679580, 26485571, 17503324, 19998422, 23336812, 11317356, 29372807, 32165640, 31589614, 28444304, 24222258, 29293505, 16950989, 17357124, 30275481, 17309986, 16570074, 28984810, 18285825, 29739340, 30609409, 20597900, 19509082, 25394566, 15689455, 31980526, 34426522, 33138774, 19204907, 34416374, Liu[article]2022, 36833263, 36362242, 34545167) (less)
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Likely pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023542.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Oct 31, 2018)
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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: SCV000893729.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Dec 13, 2018)
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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: SCV000916170.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC26A4 c.1003T>C (p.Phe335Leu) missense variant has been identified in a compound heterozygous state in two siblings with SLC26A4-related disorders, and in a heterozygous state … (more)
The SLC26A4 c.1003T>C (p.Phe335Leu) missense variant has been identified in a compound heterozygous state in two siblings with SLC26A4-related disorders, and in a heterozygous state in at least 17 individuals in whom a second variant was not identified (Campbell et al. 2001; Albert et al. 2006; Madden et al. 2007; Yang et al. 2007; Pera et al. 2008; Choi et al. 2009; Pourová et al. 2010; Landa et al. 2013; Rendtorff et al. 2013). The compound heterozygous siblings were described with clinical features of hearing loss and enlarged vestibular aqueduct (EVA), where one of the siblings had bilateral EVAs and the other sibling had unilateral EVA. Most of the heterozygous probands presented with hearing loss with EVA, and the p.Phe335Leu variant was first identified in these probands through single-gene analyses of SLC26A4. In many probands with SLC26A4-related disorders, a second disease-causing variant is not identified (Yang et al. 2009). Digenic inheritance of heterozygous variants in SLC26A4 and KCNJ10 in association with hearing loss has been reported, and the p.Phe335Leu variant has been reported in a heterozygous state in two probands who also carried a KCNJ10 variant in a heterozygous state (Yang et al. 2009; Landa et al. 2013). The p.Phe335Leu variant is reported at a frequency of 0.00307 in the South Asian population of 1000 Genomes. Functional studies showed that the SLC26A4 protein carrying the p.Phe335Leu variant traffics to the plasma membrane in a manner indistinguishable from wild type protein and has substantial residual activity, but has a reduced Cl−/I− exchange rate constant (Choi et al. 2009). Based on the collective evidence, the p.Phe335Leu variant is classified as likely 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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Likely pathogenic
(Oct 22, 2018)
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criteria provided, single submitter
Method: research
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Pendred syndrome
Affected status: yes
Allele origin:
paternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV000993594.1 First in ClinVar: Sep 26, 2019 Last updated: Sep 26, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Failure to thrive (present)
|
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Likely pathogenic
(Nov 18, 2020)
|
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: SCV000605152.3
First in ClinVar: Apr 29, 2017 Last updated: Jan 08, 2022 |
Comment:
The c.1003T>C; p.Phe335Leu variant (rs111033212) has been reported extensively in the literature in individuals with hearing loss, and many of these patients also had dilated … (more)
The c.1003T>C; p.Phe335Leu variant (rs111033212) has been reported extensively in the literature in individuals with hearing loss, and many of these patients also had dilated vestibular aqueduct (DVA) or other abnormalities of the temporal bone without goiter (Campbell 2001, Choi 2009, Madden 2007, Pera 2008, Pourova 2010, Prasad 2004). Multiple probands also had a second pathogenic variant in trans (Choi 2009 and Pera 2008). This variant segregated with bilateral hearing loss in one affected family member (Pera 2008), and functional studies indicate that the p.Phe335Leu variant causes a mild but significant reduction in transporter activity compared to wild-type (Choi 2009). This variant is found in the South Asian population with an allele frequency of 0.25% (76/30,612 alleles, including 1 homozygotes) in the Genome Aggregation Database. The phenylalanine at codon 335 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.858). Based on available information, this variant is considered to be likely pathogenic. (less)
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Uncertain significance
(May 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002569371.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
A heterozygous missense variation in exon 9 of the SLC26A4 gene that results in the amino acid substitution of Leucine for Phenalalanine at codon 335 … (more)
A heterozygous missense variation in exon 9 of the SLC26A4 gene that results in the amino acid substitution of Leucine for Phenalalanine at codon 335 was detected. The observed variant c.1003 T>C (p.Phe335Leu) the variant has a minor allele Frequency of 0.08% 1000 genomes, gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as uncertain significance (less)
Clinical Features:
Hearing impairment (present)
Age: 20-29 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Aug 29, 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
|
MGZ Medical Genetics Center
Accession: SCV002581825.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 2
Sex: female
|
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Likely pathogenic
(Jul 25, 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: SCV002583769.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
PS3_Supporting, PM3_Strong, PP1, PP3, PP4
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Pathogenic
(Apr 20, 2023)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 4
Affected status: yes
Allele origin:
paternal
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Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003918981.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
|
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175768.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense/ splice region variant c.1003T>C (p.Phe335Leu) in the SLC26A4 gene has been reported previously in a compound heterozygous and heterozygous state in individuals affected … (more)
The missense/ splice region variant c.1003T>C (p.Phe335Leu) in the SLC26A4 gene has been reported previously in a compound heterozygous and heterozygous state in individuals affected with Nonsyndromic hearing loss and enlargement of the vestibular aqueduct. Published functional studies have shown normal plasma membrane localization but a lower exchange rate constant for p.(F335L) compared to wild-type constructs (Nonose et al., 2018; Choi et al., 2009). This variant is reported with the allele frequency (0.08%) in the gnomAD and novel in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Phenylalanine at position 335 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe335Leu in SLC26A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201803.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001045245.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 335 of the SLC26A4 protein (p.Phe335Leu). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 335 of the SLC26A4 protein (p.Phe335Leu). This variant is present in population databases (rs111033212, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with deafness (PMID: 19509082, 20128824, 24051746, 25394566, 26485571). 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. This variant has been shown to cause SLC26A4-related conditions when it occurs in trans with a functionally null variant; however the effect of this variant on homozygous individuals has not been well documented in the literature. (PMID: 19578036, 19204907). ClinVar contains an entry for this variant (Variation ID: 4842). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810358.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
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Likely pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004810836.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
SLC26A4: PM3:Strong, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 23, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060075.7
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Phe335Leu variant in SLC26A4 has been reported in more than 25 probands with hearing loss, at least 19 of whom had temporal bone abnormalities, … (more)
The p.Phe335Leu variant in SLC26A4 has been reported in more than 25 probands with hearing loss, at least 19 of whom had temporal bone abnormalities, and at least 6 of whom had a second pathogenic variant in SLC26A4 (Campbell 2001 PMID 11317356, Prasad 2004 PMID 14679580, Pryor 2005 PMID 15689455, Madden 2007 PMID 17309986, Samanich 2007 PMID 17357124, Yang 2007 PMID 17503324, Pera 2008 PMID 18285825, Choi 2009 PMID 19204907, Dai 2009 PMID 19509082, Yang 2009 PMID 19426954, Pourova 2010 PMID 20597900, Rodriguez 2010 PMID 20668687, Chattaraj 2013 PMID 24051746, Landa 2013 PMID 23965030, Soh 2015 PMID 25394566, Likar 2018 PMID 29293505, LMM data). The variant also segregated with hearing loss and EVA in at least 1 affected family member (Pera 2008 PMID 18285825). Other variants at this position, p.Phe335Ser and p.Phe335Val, have been detected in individuals with hearing loss (Madden 2007 PMID 17309986, Nanose 2018 PMID 29739340), suggesting that changes to this position may not be tolerated. Furthermore, in vitro functional studies provide some evidence that the p.Phe335Leu variant may impact protein function (Choi 2009 PMID 19204907). This variant has also been identified in 0.25% (77/30778) of South Asian chromosomes, including 1 homozygote, by the Genome Aggregation Database (http://gnomAD.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and it is not known if individuals with hearing loss were excluded from the population studies included in gnomAD. In addition, a case-control comparison using Chi-squared analysis revealed a statistically significantly difference between the number of cases with the variant versus controls (p-value of <0.0001). In summary, despite its high frequency in the general population, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_Very Strong, PP1, PS3_P, PP3, BS1_Supporting. (less)
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Pathogenic
(May 01, 2009)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025291.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 07, 2016 |
Comment on evidence:
In a patient with nonsyndromic hearing loss associated with enlarged vestibular aqueduct (DFNB4; 600791), Yang et al. (2009) identified double heterozygosity for a T-to-C transition … (more)
In a patient with nonsyndromic hearing loss associated with enlarged vestibular aqueduct (DFNB4; 600791), Yang et al. (2009) identified double heterozygosity for a T-to-C transition at nucleotide 1003 of the SLC26A4 gene, resulting in a phe-to-leu substitution at codon 335 (F335L), and a missense mutation in the KCNJ10 gene (P194H; 602208.0008). The F335L mutation had been described by Pryor et al. (2005) and was been reported in 14 of 668 patients with enlarged vestibular aqueduct (EVA)-associated hearing loss but in none of 358 normal hearing controls, as described by Yang et al. (2009). Choi et al. (2009) used in vitro functional expression studies in COS-7 cells to show that the mutant F335L protein was expressed normally at the cell surface and retained function in Xenopus oocytes. The authors suggested that it may not be pathogenic as a monoallelic variant. (less)
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Uncertain significance
(-)
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809021.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(-)
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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: SCV001972971.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002569371.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians. | Kausthubham N | Human mutation | 2021 | PMID: 33502066 |
Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects. | Nonose RW | BMC medical genetics | 2018 | PMID: 29739340 |
Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss. | Likar T | PloS one | 2018 | PMID: 29293505 |
[Results of molecular genetic testing in Russian patients with Pendred syndrome and allelic disorders]. | Mironovich OL | Genetika | 2017 | PMID: 29372807 |
STRC Deletion is a Frequent Cause of Slight to Moderate Congenital Hearing Impairment in the Czech Republic. | Plevova P | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2017 | PMID: 28984810 |
A frequent oligogenic involvement in congenital hypothyroidism. | de Filippis T | Human molecular genetics | 2017 | PMID: 28444304 |
Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain. | Bassot C | Biochimie | 2017 | PMID: 27771369 |
Atypical patterns of segregation of familial enlargement of the vestibular aqueduct. | Muskett JA | The Laryngoscope | 2016 | PMID: 26485571 |
Evaluation of genotype-phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome. | Soh LM | European journal of endocrinology | 2015 | PMID: 25394566 |
Use of mobile phones as a tool for weight loss: a systematic review. | Aguilar-Martínez A | Journal of telemedicine and telecare | 2014 | PMID: 24875928 |
Hearing impairment in Estonia: an algorithm to investigate genetic causes in pediatric patients. | Teek R | Advances in medical sciences | 2013 | PMID: 24222258 |
Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct. | Chattaraj P | JAMA otolaryngology-- head & neck surgery | 2013 | PMID: 24051746 |
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 |
SLC26A4 mutation frequency and spectrum in 109 Danish Pendred syndrome/DFNB4 probands and a report of nine novel mutations. | Rendtorff ND | Clinical genetics | 2013 | PMID: 23336812 |
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 |
Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without Enlarged Vestibular Aqueduct (EVA). | Pourová R | Annals of human genetics | 2010 | PMID: 20597900 |
Two missense mutations in SLC26A4 gene: a molecular and functional study. | Rebeh IB | Clinical genetics | 2010 | PMID: 20128824 |
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 |
Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. | Yang T | American journal of human genetics | 2009 | PMID: 19426954 |
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 |
A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss. | Pera A | European journal of human genetics : EJHG | 2008 | PMID: 18285825 |
Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4). | Yang T | American journal of human genetics | 2007 | PMID: 17503324 |
Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. | Samanich J | American journal of medical genetics. Part A | 2007 | PMID: 17357124 |
The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct. | Madden C | Archives of otolaryngology--head & neck surgery | 2007 | PMID: 17309986 |
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 |
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 |
Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations. | Campbell C | Human mutation | 2001 | PMID: 11317356 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fd54e511-37fc-437e-bf54-4757947ec10f | - | - | - | - |
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Text-mined citations for rs111033212 ...
HelpRecord last updated Apr 20, 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.