ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.412G>T (p.Val138Phe)

gnomAD frequency: 0.00019  dbSNP: rs111033199
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000005106 SCV000840515 pathogenic Pendred syndrome 2018-09-19 reviewed by expert panel curation The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID: 17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID: 12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824762 SCV000060148 pathogenic Rare genetic deafness 2020-09-16 criteria provided, single submitter clinical testing The p.Val138Phe variant in SLC26A4 has been reported in more than 20 individuals with clinical features of Pendred syndrome or DFNB4 hearing loss, at least 10 of whom were homozygous or compound heterozygous (Borck 2003 PMID: 12788906, Campbell 2001 PMID: 11317356, Coyle 1998 PMID: 9618167, de Moraes 2013 PMID: 23273637, Gonzalez Trevino 2001 PMID: 11375792, Kandasamy 2011 PMID: 21551164, Pourova 2010 PMID: 20597900, Pryor 2005 PMID: 15689455, Taylor 2002 PMID: 11932316, Van Hauwe 1998 PMID: 9618166, LMM data). It has been identified in 0.03% (38/126540) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs111033199); however, this low frequency is consistent with the carrier frequency in the general population. In vitro functional studies provide some evidence that the p.Val138Phe variant may impact protein function (Taylor 2002 PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for Pendred syndrome or nonsyndromic hearing loss in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_VeryStrong, PS4, PM2_Supporting, PS3_Supporting.
Illumina Laboratory Services, Illumina RCV000272658 SCV000466080 pathogenic SLC26A4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing Across a selection of the available literature, the SLC26A4 c.412G>T (p.Val138Phe) missense variant has been identified in a total of 23 patients with hearing loss or Pendred syndrome, including in four in a homozygous state, 14 in a compound heterozygous state and five in a heterozygous state in whom a second variant was not identified. The variant was also found in a heterozygous state in at least two unaffected family members (Van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Gonzales-Trevino et al. 2001; Taylor et al. 2002; Borck et al. 2003; Pryor et al. 2005; Pera et al. 2008; Kandasamy et al. 2011; Landa et al. 2013). Segregation with disease is reported to have been shown in several families (Van Hauwe et al. 1998; Gonzales-Trevino et al. 2001). The variant was absent from 214 controls and is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Val138 residue is conserved among several other related sulfate transporter genes from different species. Functional studies have shown that the p.Val138Phe variant protein is retained in the endoplasmic reticulum and fails to reach the cell membrane leading to loss of protein activity (Taylor et al. 2002). Based on the collective evidence, the p.Val138Phe 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.
GeneDx RCV000413949 SCV000490808 pathogenic not provided 2020-06-29 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect due to aberrant protein processing, with retention of pendrin in the endoplasmic reticulum and absence of proper pendrin assembly at the cell membrane (Taylor et al., 2002); Common variant in Caucasian populations, accounting for approximately 12% of pathogenic alleles in published studies of Western European individuals (Tsukada et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (Oza et al., 2018; ClinVar SCV000840515.3; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9618166, 21551164, 17503324, 23336812, 19608655, 11932316, 26969326, 23273637, 12788906, 26744121, 29986705, 30473558, 30762457, 29320412, 29984802, 27771369, 18285825, 26683941, 25999548, 24224479, 16570074, 15689455, 23965030, 20597900, 31980526, 31589614)
Fulgent Genetics, Fulgent Genetics RCV000036493 SCV000611320 pathogenic Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome 2022-02-04 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000413949 SCV000862124 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing
Invitae RCV000413949 SCV000937942 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the SLC26A4 protein (p.Val138Phe). This variant is present in population databases (rs111033199, gnomAD 0.03%). This missense change has been observed in individuals with Pendred syndrome (PMID: 9618166, 11932316, 12788906, 21551164, 23273637, 24224479, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4835). 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 80%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV000005106 SCV001194102 pathogenic Pendred syndrome 2019-12-20 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.412G>T(V138F) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 19204907, 15355436, 11375792, 21551164, 15689455, 12788906, 23273637, 19017801, 9618167, 11932316, 9070918 and 9618166. Classification of NM_000441.1(SLC26A4):c.412G>T(V138F) 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.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375189 SCV001571795 pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Supporting, PM5_Moderate, PP3_Supporting
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital RCV000005106 SCV001792213 pathogenic Pendred syndrome criteria provided, single submitter research in compound heterozygosis with the c.554G>C variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001813952 SCV002061650 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2021-10-21 criteria provided, single submitter clinical testing PM3_Very_Strong, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4, PS3_Supporting
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000005106 SCV003935255 pathogenic Pendred syndrome 2020-05-15 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000413949 SCV004025148 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV001813952 SCV004201813 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-10-30 criteria provided, single submitter clinical testing
OMIM RCV000005106 SCV000025282 pathogenic Pendred syndrome 2003-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000005106 SCV001455796 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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