ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1226G>A (p.Arg409His) (rs111033305)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036428 SCV000060083 pathogenic Rare genetic deafness 2015-08-26 criteria provided, single submitter clinical testing The p.Arg409His variant in SLC26A4 has been identified in >20 individuals with h earing loss and EVA and/or goiter who were homozygous or compound heterozygous w ith a disease-causing variant on the remaining allele. In addition, the p.Arg40 9His variant segregated with disease in at least three affected siblings (Blons 2004, Chai 2013, Fugazzola 2007, Pera 2008, Pera 2008, Rendtorff 2013, Van Hauwe 1998, LMM data). This variant has been identified in 13/66658 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033305); however, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 hearing loss or Pendred syndrome in an autos omal recessive manner based on multiple co-occurrences with pathogenic SLC26A4 v ariants in individuals with hearing loss.
GeneDx RCV000424441 SCV000514663 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing The R409H variant has been published previously in association with Pendred syndrome (Pourová et al., 2010; Bademci et al., 2015; Pang et al., 2015). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, functional studies have shown that R409H impairs the activity of the SLC26A4 protein in comparison to wild type (Gillam et al., 2005). Missense variants in the same residue (R409C/L/P) and in nearby residues (T404I, A406T, T410M, A411T/P, V412I, Q413P/R, E414K) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506765 SCV000605150 pathogenic not specified 2017-03-02 criteria provided, single submitter clinical testing
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000515653 SCV000611813 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
Invitae RCV000424441 SCV000936543 pathogenic not provided 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 409 of the SLC26A4 protein (p.Arg409His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs111033305, ExAC 0.02%). This variant has been observed as homozygous or in combination with another SLC26A4 variant in individuals affected with deafness or Pendred syndrome (PMID: 11919333, 24224479, 19786220, 20597900, 16053392, 21961810, 26100058, 26226137) and in one of these individuals it was observed on the opposite chromosome (in trans) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 43496). Experimental studies have shown that this missense change disrupts iodine efflux from cells (PMID: 16053392). This variant disrupts the p.Arg409 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 18167283, 23185506, 25372295), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000169222 SCV001194157 pathogenic Pendred syndrome 2020-01-06 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.1226G>A(R409H) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 17718863, 17443271, 15355436, 18813951, 11919333, 19786220, 16053392, 21961810, 24224479 and 19017801. Classification of NM_000441.1(SLC26A4):c.1226G>A(R409H) 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.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000515653 SCV001244766 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2018-04-09 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000441.1(SLC26A4):c.1226G>A, has been identified in exon 10 of 21 of the SLC26A4 gene. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 409 of the protein (NP_000432.1(SLC26A4):p.(Arg409His)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the sulfate permease superfamily. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.009% (0 homozygotes). The variant has been previously described as pathogenic multiple times (Kahrizi K. et al. (2009), Blons H. et al. (2004); Bogazzi F. et al. (2014), Chai Y. et al. (2013)). It has also been shown to segregate with the disease in at least 1 family (Fugazzola L. et al. 2007). Additionally, it has been shown that the mutation impairs pendrin (an anion exhange protein) function. Functional studies demonstrate that mutants lose the ability to mediate iodide efflux (Gillaim M. et al. 2005). Three different variants in the same codon resulting in a change to cysteine, proline and leucine have also been shown to cause Pendred syndrome and enlarged vestibular aqueduct (ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515653 SCV000902370 likely pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV000515653 SCV000994885 affects Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided clinical testing in vitro experiment
The Core Laboratory in Medical Center of Clinical Research,Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine RCV000169222 SCV001438735 pathogenic Pendred syndrome 2020-05-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000169222 SCV001455810 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291345 SCV001479819 likely pathogenic Autosomal recessive nonsyndromic deafness no assertion criteria provided research

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