rs145254330
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Variant summary
Our verdict is Pathogenic. Variant got -1 ACMG points: 8P and 9B. PP3PP4PM3BS3_SupportingBA1PP1_Strong
This summary comes from the ClinGen Evidence Repository: The c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel (LMM) (PP4). The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID:27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132727/MONDO:0010134/005
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 missense
NM_000441.2 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 4.50
Genes affected
SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got -1 ACMG points.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC26A4 | NM_000441.2 | c.349C>T | p.Leu117Phe | missense_variant | 4/21 | ENST00000644269.2 | NP_000432.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC26A4 | ENST00000644269.2 | c.349C>T | p.Leu117Phe | missense_variant | 4/21 | NM_000441.2 | ENSP00000494017 | P1 | ||
| SLC26A4 | ENST00000440056.1 | c.349C>T | p.Leu117Phe | missense_variant | 4/4 | 4 | ENSP00000394760 |
Frequencies
GnomAD3 genomes 0.000197 AC: 30AN: 152040Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000326 AC: 82AN: 251428Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135884
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GnomAD4 exome AF: 0.000331 AC: 484AN: 1460958Hom.: 0 Cov.: 29 AF XY: 0.000336 AC XY: 244AN XY: 726838
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GnomAD4 genome 0.000197 AC: 30AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17AN XY: 74390
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Uncertain:3Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3Uncertain:1Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A heterozygous missense variant was identified, NM_000441.1(SLC26A4):c.349C>T in exon 4 of 21 of the SLC26A4 gene. This substitution is predicted to create a minor amino acid change from a leucine to a phenylalanine at position 117 of the protein; NP_000432.1(SLC26A4):p.(Leu117Phe). The leucine at this position has very high conservation (100 vertebrates, UCSC), and is located within the sulfate transp domain (PDB). In silico software predicts this variant to be damaging (PolyPhen2, MutationAssessor, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a global population frequency of 0.03% (83 heterozygotes, 0 homozygotes) with an Ashkenazi Jewish sub-population frequency of 0.5%. This variant has been previously reported as likely pathogenic in patients with hearing loss (ClinGen Hearing Loss Variant Curation Expert Panel). Functional analysis using human HeLa and HEK cells shows that this variant resulted in normal cellular localisation of the mutant protein and iodide efflux of the cells (Taylor, J. et al. (2002)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. - |
| Pathogenic, no assertion criteria provided | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Feb 19, 2016 | Congenital, profound HL - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| other, no assertion criteria provided | in vitro;literature only | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | Benign effect in vitro experiment Benign effect in vitro experiment |
Pendred syndrome Pathogenic:3Uncertain:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Feb 19, 2016 | Congenital, profound HL - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Nov 22, 2022 | The c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel (LMM) (PP4). The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2023 | Variant summary: SLC26A4 c.349C>T (p.Leu117Phe) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) 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 0.00033 in 251428 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00033 vs 0.0035), allowing no conclusion about variant significance. c.349C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with hearing loss (Dahl_2013, Sloan-Heggen_2016, Brownstein_2020). These data indicate that the variant is very likely to be associated with disease. Two seperate publications have shown the variant behaves similarly to wild-type when expressed in HEK293T/HeLa cells (Taylor_2002, Wasano_2020). Ten ClinVar submitters, including one expert panel, have assessed the variant since 2014: two classified the variant as uncertain significance, five classified the variant as likely pathogenic, three (including the expert panel) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 117 of the SLC26A4 protein (p.Leu117Phe). This variant is present in population databases (rs145254330, gnomAD 0.5%). This missense change has been observed in individuals with profound congenital deafness (PMID: 23555729, 26969326, 33111345, 34410491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43555). 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 have shown that this missense change does not substantially affect SLC26A4 function (PMID: 11932316, 31599023, 32165640). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2024 | Reported in the published literature and at GeneDx in the heterozygous state in multiple individuals with hearing loss and enlarged vestibular aqueduct in whom a second pathogenic variant was not identified; however, lack of a second pathogenic variant in SLC26A4-associated hearing loss is not an uncommon finding (PMID: 26969326, 11932316, 16570074); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19608655, 25262649, 27771369, 11932316, 16570074, 10700480, 31589614, 31599023, 36147510, 30245029, 14508505, 34410491, 16950989, 33111345, 30311386, 33879512, 36233414, 37108562, 38474007, 26969326) - |
Rare genetic deafness Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 08, 2020 | The p.Leu117Phe variant in SLC26A4 has been previously reported in 8 individuals with hearing loss, 6 of whom had enlarged vestibular aqueducts, and 5 of whom had a second SLC26A4 variant on the remaining allele (Reardon 2000, Albert 2006, Sloan-Heggen 2016, ClinVar SCV000282015.1, LMM unpublished data). This variant was classified as Likely Pathogenic on Sep 26, 2018 by the ClinGen-approved Hearing Loss expert panel (Variation ID 43555). This variant has also been reported in the homozygous state in 2 Ashkenazi Jewish families with hearing loss (Brownstein 2020, bioRxiv 2020.06.11.144790; doi: https://doi.org/10.1101/2020.06.11.144790). The variant segregated in 2 affected family members; however, one affected individual was heterozygous only for the variant. This variant is also present in 0.5% (54/10368) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145254330). However, given the lack of understanding of Pendred syndrome prevalence in the Ashkenazi Jewish population, this allele frequency was not considered strong enough conflicting evidence to counter the pathogenic evidence. Two in vitro functional study demonstrated that the variant did not impact localization of the protein to the cell membrane or iodide efflux capacity; however, not all ion transport functions of the mutant proteins were assessed (Taylor 2002, Wasano 2020). In addition, the leucine (Leu) residue at position 117 is highly conserved across mammals and distant species, suggesting that variants at this position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP criteria applied: PM3_VeryStrong, PP1, PP4, PP3, BS1, BS3_Supporting. - |
SLC26A4-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 20, 2024 | The SLC26A4 c.349C>T variant is predicted to result in the amino acid substitution p.Leu117Phe. This variant has been reported along with a second causal variant in a patient with hearing loss (Table S3, Sloan-Heggen et al 2016. PubMed ID: 26969326) and in three patients in which a second causal variant was not identified (Reardon et al 2000. PubMed ID: 10700480; Taylor et al 2002. PubMed ID: 11932316; Albert et al 2006. PubMed ID: 16570074). This variant has also been reported in the homozygous state in four patients with hearing loss from two families, being heterozygous in four unaffected and one affected individual (Figure S1, Brownstein et al 2020. PubMed ID: 33111345). A functional study found this variant had iodide efflux levels similar to wildtype (Taylor et al 2002. PubMed ID: 11932316). This variant is reported in 0.52% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is classified as likely pathogenic for autosomal recessive Pendred syndrome by the ClinGen Hearing Loss Variant Curation Expert Panel, in part based on internal data from other clinical testing laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/43555/). This variant is interpreted as likely pathogenic. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 19, 2022 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2018 | The p.Leu117Phe variant (rs145254330) has been reported in multiple individuals with non-syndromic hearing loss (Reardon 2000, Albert 2006, Sloan-Heggen 2016); however, it has never been observed in trans with any pathogenic allele, and functional studies revealed no difference in protein localization or channel function when compared to wild-type SLC26A4 protein (Taylor 2002). Furthermore, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.51% (identified in 52 out of 10,150 chromosomes), and is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 43555). Taken together, the clinical significance of the p.Leu117Phe variant cannot be determined with certainty. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at