ClinVar Miner

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

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Total submissions: 7
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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.
Counsyl RCV000169222 SCV000220487 pathogenic Pendred syndrome 2014-07-08 criteria provided, single submitter literature only
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 Enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
Invitae RCV000424441 SCV000936543 pathogenic not provided 2018-10-21 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.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515653 SCV000902370 likely pathogenic Enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control

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