rs80338848
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000441.2(SLC26A4):c.707T>C(p.Leu236Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00049 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 missense
NM_000441.2 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.54
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 14 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity S26A4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000441.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant 7-107675051-T-C is Pathogenic according to our data. Variant chr7-107675051-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107675051-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC26A4 | NM_000441.2 | c.707T>C | p.Leu236Pro | missense_variant | 6/21 | ENST00000644269.2 | NP_000432.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC26A4 | ENST00000644269.2 | c.707T>C | p.Leu236Pro | missense_variant | 6/21 | NM_000441.2 | ENSP00000494017 | P1 |
Frequencies
GnomAD3 genomes 0.000329 AC: 50AN: 152190Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000274 AC: 69AN: 251476Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135918
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GnomAD4 exome AF: 0.000487 AC: 712AN: 1461798Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 351AN XY: 727204
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GnomAD4 genome 0.000329 AC: 50AN: 152190Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 18AN XY: 74354
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 02, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SLC26A4 p.L236P variant has been reported in multiple homozygous or compound heterozygous individuals with hearing loss or hearing impairment (Yan_2017_PMID:28273078; Tang_2015_PMID:25991456; Pryor_2005_PMID:15689455; Pourova_2010_PMID:20597900; Busi_2012_PMID:22717225; Campbell_2001_PMID:11317356; Siem_2010_PMID:20553101; Van Hauwe_1998_PMID:9618166). The variant was identified in dbSNP (ID: rs80338848) and ClinVar (classified as pathogenic by Invitae, GeneDx, EGL Genetic Diagnostics and nine other submitters). The variant was identified in control databases in 83 of 282766 chromosomes (0 homozygous) at a frequency of 0.0002935, and was observed at the highest frequency in the European (non-Finnish) population in 77 of 129104 chromosomes (freq: 0.0005964) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L236 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies have shown that this variant causes protein mislocalization and impaired iodide/chloride transport activity compared to wild type (Scott_2000_PMID:10861298, Rotman-Pikielny_2002_PMID:12354788, Yoon_2008_PMID:18310264). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 03, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| 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 proline, which is neutral and non-polar, at codon 236 of the SLC26A4 protein (p.Leu236Pro). This variant is present in population databases (rs80338848, gnomAD 0.06%). This missense change has been observed in individual(s) with Pendred syndrome and hearing loss (PMID: 9618166, 15689455, 20553101, 20597900, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4817). 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 affects SLC26A4 function (PMID: 10861298, 12354788, 18310264). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2020 | Published functional studies demonstrate a damaging effect due to improper intracellular localization of pendrin and loss of pendrin-induced iodide and chloride transport (Scott et al., 2000; Yoon et al., 2008); Common variant in Caucasian populations, accounting for approximately 10% of pathogenic alleles in published studies of Western European individuals (Tsukada et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 26969326, 11317356, 31827275, 12354788, 10861298, 18310264, 9618166, 26022370, 10700480, 20553101, 9618167, 22717225, 27771369, 31163360, 15689455, 20597900, 25999548, 31980526, 31589614) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital | Aug 22, 2023 | - - |
Pendred syndrome Pathogenic:6Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 22, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000441.1(SLC26A4):c.707T>C(L236P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 9618167, 9618166, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.707T>C(L236P) 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | 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 leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 83 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 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 sulfate permease family (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants in individuals with European 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 - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
SLC26A4-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 21, 2018 | The SLC26A4 c.707T>C (p.Leu236Pro) missense variant is well described in the literature and is one of the three most common pathogenic variants in SLC26A4, which together account for 50% of the disease-causing alleles in probands with Pendred syndrome of northern European descent (Alasti et al. 2014; Tsukada et al. 2015). Across a selection of available literature, the p.Leu236Pro variant has been reported in at least four individuals in a homozygous state, 13 individuals in a compound heterozygous state, and one individual in a heterozygous state, all affected with Pendred syndrome (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001). The variant has also been reported in individuals affected with hearing loss, including two in a compound heterozygous state and five in a heterozygous state (Yan et al. 2017). Campbell et al. (2001) demonstrated segregation with disease in at least one multiplex family with temporal bone abnormalities. Haplotype analysis suggests a common founder effect for this variant (van Hauwe et al. 2008; Coyle et al. 1998). The p.Leu236Pro variant was absent from 257 control individuals (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Yan et al. 2017) and is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. Functional studies by Rotman-Pikielny et al. (2002) demonstrated that the variant protein is retained in the endoplasmic reticulum (ER) whereas the wild type protein targets to the plasma membrane. Yoon et al. (2008) confirmed the initial localization of the p.Leu236Pro variant protein in the ER and showed that after time, the protein was concentrated at the centrosome. They further determined that Cl-/HCO3- ion exchange activity of the variant protein was notably decreased, and that the variant was not temperature sensitive. Based on collective evidence, the p.Leu236Pro 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 15, 2024 | The SLC26A4 c.707T>C variant is predicted to result in the amino acid substitution p.Leu236Pro. This variant has been reported to be causative for Pendred syndrome (van Hauwe et al 1998. PubMed ID: 9618166; Campbell et al 2001. PubMed ID: 11317356; Pourová et al 2010. PubMed ID: 20597900). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Hearing impairment Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Supporting, BP4_Supporting - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 04, 2017 | The p.Leu236Pro variant in SLC26A4 has been reported in at least 15 individuals with either nonsyndromic hearing loss or Pendred syndrome who were homozygous or compound heterozygous, and it segregated in 4 affected family members from 2 fa milies (Busi 2012, Pryor 2005, Pourova 2010, Siem 2010, Van Hauwe 1998, LMM data ). One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002). The p.Leu236Pr o variant has been identified in 0.1% (78/126638) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 80338848). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on bi-allelic occurrences in multiple affected indi viduals, segregation studies, functional evidence, and low frequency in the gene ral population. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Sup porting. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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