ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1489G>A (p.Gly497Ser) (rs111033308)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036444 SCV000060099 pathogenic Rare genetic deafness 2011-12-23 criteria provided, single submitter clinical testing The Gly497Ser variant in SLC26A4 has been reported in six probands with Pendred syndrome or sensorineural hearing loss (Scott 2000, Bogazzi 2004, Gardner 2006, Jiang 2010, Li 1998, Pera 2008, Prasad 2004, Yoon 2008). Four of these probands were homozygous or compound heterozygous. Functional studies have shown that the Gly487Ser variant inhibits protein function (Scott 2000, Yoon 2008). In summary , this variant meets our criteria to be classified as pathogenic.
GeneDx RCV000489866 SCV000577405 pathogenic not provided 2017-03-30 criteria provided, single submitter clinical testing The G497S pathogenic variant in the SLC26A4 gene has been reported previously in the homozygous state in multiple affected individuals in a family with non-syndromic hearing loss and in the compound heterozygous state with another SLC26A4 variant in an individual with hearing loss and enlarged vestibular aqueduct (Li et al., 1998; Sakuma et al., 2016). Studies have demonstrated this variant significantly reduces ion transport and abolishes the complex glycosylation and exchange activities of the pendrin protein (Scott et al., 2000; Yoon et al., 2008). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G497S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same amino acid position (G497R) and in nearby residues (I491T and G493W) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014). We interpret G497S as a pathogenic variant.
Invitae RCV000489866 SCV001215510 pathogenic not provided 2020-06-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 497 of the SLC26A4 protein (p.Gly497Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs111033308, ExAC 0.01%). This variant has been observed in individuals affected with sensorineural hearing loss and enlarged vestibular aqueduct, and it segregated with disease in related individuals (PMID: 9500541, 26763877, 28964290). ClinVar contains an entry for this variant (Variation ID: 4816, 43510). This variant has been reported to affect SLC26A4 protein function (PMID: 10861298, 18310264). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000489866 SCV001250493 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375472 SCV001572145 uncertain significance Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PM2_Moderate, PP3_Supporting
Counsyl RCV000169242 SCV000220517 pathogenic Pendred syndrome 2018-02-21 no assertion criteria provided clinical testing
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV001004645 SCV000994895 affects Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided clinical testing in vitro experiment
Natera, Inc. RCV000169242 SCV001459928 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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