Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (ClinVar ID: VCV000996638, PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23918157). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:32447495,9618166). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.985>=0.6, 3CNET: 0.984>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000441.2(SLC26A4):c.416G>T (p.Gly139Val)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000441.2(SLC26A4):c.416G>T (p.Gly139Val)
Variation ID: 996638 Accession: VCV000996638.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q22.3 7: 107674164 (GRCh38) [ NCBI UCSC ] 7: 107314609 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 20, 2021 Jun 29, 2024 Mar 21, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000441.2:c.416G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000432.1:p.Gly139Val missense NC_000007.14:g.107674164G>T NC_000007.13:g.107314609G>T NG_008489.1:g.18530G>T - Protein change
- G139V
- Other names
- -
- Canonical SPDI
- NC_000007.14:107674163:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SLC26A4 | - | - |
GRCh38 GRCh37 |
1383 | 1582 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001291245.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 20, 2022 | RCV001378586.7 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Mar 21, 2024 | RCV001824946.6 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 9, 2023 | RCV002051933.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318847.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (ClinVar ID: VCV000996638, PMID:19287372). The … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (ClinVar ID: VCV000996638, PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23918157). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:32447495,9618166). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.985>=0.6, 3CNET: 0.984>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
|
|
|
Pathogenic
(Aug 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001576188.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs756272252, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral … (more)
This variant is present in population databases (rs756272252, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the SLC26A4 protein (p.Gly139Val). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 19287372, 23918157, 25317404, 31700827). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly139 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 9618166), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 996638). (less)
|
|
|
Likely pathogenic
(Mar 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pendred syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074331.5
First in ClinVar: Feb 12, 2022 Last updated: Jun 29, 2024 |
Comment:
Variant summary: SLC26A4 c.416G>T (p.Gly139Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547; also described as the third transmembrane … (more)
Variant summary: SLC26A4 c.416G>T (p.Gly139Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547; also described as the third transmembrane domain of Pendrin in Reiisi_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site and two predict the variant weakens this site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.9e-05 in 257564 control chromosomes (gnomAD and publication data). c.416G>T has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss (Anwar_2009, Yan_2013, Chai_2013, Reiisi_2014, Koohiyan_2021, Wu_2022) and this variant co-segregated with the disease in at least two families (Anwar_2009, Reiisi_2014). These data indicate that the variant is likely to be associated with disease. Additionally, missense variants in the same residue (G139A and G139E) have been reported in patients with Pendred syndrome in the Human Gene Mutation Database (e.g. Liu_2020, PMID: 9618166), supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23918157, 28941661, 19287372, 27771369, 31971949, 31700827, 32447495, 26683941, 26100058, 25317404, 30303587, 23296490, 33614372, 35982127). ClinVar contains an entry for this variant (Variation ID: 996638). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201937.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
non-syndromic autosomal recessive hearing loss
Affected status: yes
Allele origin:
inherited
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479670.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
|
|
|
Likely pathogenic
(May 04, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Pendred syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002079969.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This variant is present in population databases (rs756272252, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the SLC26A4 protein (p.Gly139Val). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 19287372, 23918157, 25317404, 31700827). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly139 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 9618166), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 996638).
Comment:
Variant summary: SLC26A4 c.416G>T (p.Gly139Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547; also described as the third transmembrane domain of Pendrin in Reiisi_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site and two predict the variant weakens this site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.9e-05 in 257564 control chromosomes (gnomAD and publication data). c.416G>T has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss (Anwar_2009, Yan_2013, Chai_2013, Reiisi_2014, Koohiyan_2021, Wu_2022) and this variant co-segregated with the disease in at least two families (Anwar_2009, Reiisi_2014). These data indicate that the variant is likely to be associated with disease. Additionally, missense variants in the same residue (G139A and G139E) have been reported in patients with Pendred syndrome in the Human Gene Mutation Database (e.g. Liu_2020, PMID: 9618166), supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23918157, 28941661, 19287372, 27771369, 31971949, 31700827, 32447495, 26683941, 26100058, 25317404, 30303587, 23296490, 33614372, 35982127). ClinVar contains an entry for this variant (Variation ID: 996638). Based on the evidence outlined above, the variant was classified as likely pathogenic.
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. |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (ClinVar ID: VCV000996638, PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23918157). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:32447495,9618166). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.985>=0.6, 3CNET: 0.984>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant is present in population databases (rs756272252, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the SLC26A4 protein (p.Gly139Val). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 19287372, 23918157, 25317404, 31700827). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly139 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 9618166), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 996638).
Comment:
Variant summary: SLC26A4 c.416G>T (p.Gly139Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547; also described as the third transmembrane domain of Pendrin in Reiisi_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site and two predict the variant weakens this site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.9e-05 in 257564 control chromosomes (gnomAD and publication data). c.416G>T has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss (Anwar_2009, Yan_2013, Chai_2013, Reiisi_2014, Koohiyan_2021, Wu_2022) and this variant co-segregated with the disease in at least two families (Anwar_2009, Reiisi_2014). These data indicate that the variant is likely to be associated with disease. Additionally, missense variants in the same residue (G139A and G139E) have been reported in patients with Pendred syndrome in the Human Gene Mutation Database (e.g. Liu_2020, PMID: 9618166), supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23918157, 28941661, 19287372, 27771369, 31971949, 31700827, 32447495, 26683941, 26100058, 25317404, 30303587, 23296490, 33614372, 35982127). ClinVar contains an entry for this variant (Variation ID: 996638). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular diagnose of a large hearing loss population from China by targeted genome sequencing. | Wu J | Journal of human genetics | 2022 | PMID: 35982127 |
| Molecular diagnosis of SLC26A4-related hereditary hearing loss in a group of patients from two provinces of Iran. | Koohiyan M | Intractable & rare diseases research | 2021 | PMID: 33614372 |
| Next-generation sequencing-based mutation analysis of genes associated with enlarged vestibular aqueduct in Chinese families. | Liu Y | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2020 | PMID: 32447495 |
| Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene. | Hasnain MJU | PloS one | 2020 | PMID: 31971949 |
| Screening of 10 DFNB Loci Causing Autosomal Recessive Non-Syndromic Hearing Loss in Two Iranian Populations Negative for GJB2 Mutations. | Koohiyan M | Iranian journal of public health | 2019 | PMID: 31700827 |
| Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. | Richard EM | Human mutation | 2019 | PMID: 30303587 |
| Molecular analysis of human solute carrier SLC26 anion transporter disease-causing mutations using 3-dimensional homology modeling. | Rapp C | Biochimica et biophysica acta. Biomembranes | 2017 | PMID: 28941661 |
| Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain. | Bassot C | Biochimie | 2017 | PMID: 27771369 |
| Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis. | Lu YJ | Medicine | 2015 | PMID: 26683941 |
| Mono-allelic mutations of SLC26A4 is over-presented in deaf patients with non-syndromic enlarged vestibular aqueduct. | Pang X | International journal of pediatric otorhinolaryngology | 2015 | PMID: 26100058 |
| The Study of SLC26A4 Gene Causing Autosomal Recessive Hearing Loss by Linkage Analysis in a Cohort of Iranian Populations. | Reiisi S | International journal of molecular and cellular medicine | 2014 | PMID: 25317404 |
| Molecular etiology of hearing impairment associated with nonsyndromic enlarged vestibular aqueduct in East China. | Chai Y | American journal of medical genetics. Part A | 2013 | PMID: 23918157 |
| The effect of GJB2 and SLC26A4 gene mutations on rehabilitative outcomes in pediatric cochlear implant patients. | Yan YJ | European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | 2013 | PMID: 23296490 |
| SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis. | Anwar S | Journal of human genetics | 2009 | PMID: 19287372 |
| Two frequent missense mutations in Pendred syndrome. | Van Hauwe P | Human molecular genetics | 1998 | PMID: 9618166 |
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Text-mined citations for rs756272252 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.