ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1334T>G (p.Leu445Trp) (rs111033307)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036437 SCV000060092 pathogenic Rare genetic deafness 2010-09-27 criteria provided, single submitter clinical testing The p.Leu445Trp variant has been frequently reported in the literature and is kn own to be associated with the clinical features of DFNB4/Pendred syndrome (Van H auwe 1998, Cama 2009, Choi 2009, Kahrizi 2009, Lopez-Bigas 2001, Masmoudi 2000, Pera 2008, Wilch 2006). Therefore, this variant meets our criteria to be classif ied as pathogenic for DFNB4/Pendred syndrome in an autosomal recessive manner.
GeneDx RCV000413198 SCV000490810 pathogenic not provided 2015-04-08 criteria provided, single submitter clinical testing The L445W missense variant has been reported previously in association with Pendred syndrome (Van Hauwe et al., 1998; Choi et al., 2009). In vitro functional studies demonstrated that the presence of the L445W variant resulted in the loss of glycosylation of the pendrin protein (Rebeh et al., 2010). We interpret the L445W variant as pathogenic.
Invitae RCV000413198 SCV000947483 pathogenic not provided 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with tryptophan at codon 445 of the SLC26A4 protein (p.Leu445Trp). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and tryptophan. This variant is present in population databases (rs111033307, ExAC 0.02%). This variant has been observed in individuals affected with Pendred syndrome and clinical features with Pendred syndrome (PMID: 9618166, 24224479, 20128824, 19204907, 26752218). ClinVar contains an entry for this variant (Variation ID: 4829). Experimental studies have shown that this missense change disrupts Pendrin (SLC26A4) protein function and localization in vitro (PMID: 20128824, 19204907, 26752218). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000005100 SCV001163095 pathogenic Pendred syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000005100 SCV001193884 pathogenic Pendred syndrome 2019-12-24 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.1334T>G(L445W) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18285825, 15355436, 24224479, 9618166, 19204907, 16570074, 20128824 and 23273637. Classification of NM_000441.1(SLC26A4):c.1334T>G(L445W) 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001004641 SCV001736966 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct criteria provided, single submitter clinical testing
OMIM RCV000005100 SCV000025276 pathogenic Pendred syndrome 2009-04-01 no assertion criteria provided literature only
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV001004641 SCV000994891 affects Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided clinical testing in vitro experiment
Natera, Inc. RCV000005100 SCV001459926 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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