ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1246A>C (p.Thr416Pro) (rs28939086)

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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 RCV000824771 SCV000060087 pathogenic Rare genetic deafness 2017-11-22 criteria provided, single submitter clinical testing The p.Thr416Pro variant in SLC26A4 has been reported in at least 10 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aque ducts (EVA), all of whom were compound heterozygous, and segregated with disease in 3 affected relatives from 2 families (Campbell 2001, Ladsous 2014, LMM data) . It has been identified in 0.04% (48/126104) of European chromosomes by the Gen ome Aggregation Database (gnomAD,; dbSNP rs289 39086). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a carrier frequency for recessive heari ng loss. Computational prediction tools and conservation analysis suggest that t he p.Thr416Pro variant may impact the protein. In summary, this variant meets cr iteria to be classified as pathogenic for Pendred syndrome or nonsyndromic heari ng loss in an autosomal recessive manner based on multiple biallelic occurrences in individuals with hearing loss and segregation in affected relatives. ACMG/AM P Criteria applied: PM3_VeryStrong; PP1_Moderate; PP3; PP4.
GeneDx RCV000435157 SCV000514664 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing The T416P variant in the SLC26A4 gene has been reported previously either in the homozygous state or with another SLC26A4 variant in multiple individuals with suspected Pendred syndrome (van Hauwe et al., 1998; Napiontek et al., 2004; Ladsous et al., 2014). The variant is observed in 48/126104 (0.0381%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The T416P 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies show that T416P is associated with decreased or absent pendrin-induced chloride, iodide, and bicarbonate transport (Scott et al., 2000; Yoon et al., 2008). Missense variants in nearby residues (A411P/T, Q413R/P, E414K, S415G/R, T420I, Q421K/P/R/L) 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. We consider this variant to be pathogenic.
Counsyl RCV000005087 SCV000677993 pathogenic Pendred syndrome 2015-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036432 SCV000893731 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779525 SCV000916172 pathogenic SLC26A4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The SLC26A4 c.1246A>C (p.Thr416Pro) missense variant is a well-documented pathogenic variant accounting for at least 15% of disease alleles in individuals with a confirmed diagnosis of Pendred syndrome who are of northern European descent (Alasti et al. 2014). Across a selection of the available literature, the p.Thr416Pro variant has been identified in a homozygous state in four patients, in a compound heterozygous state in 45 patients and in a heterozygous state in five patients (Coyle et al. 1998; van Hauwe et al. 1998; Campbell et al, 2001; Napiontek et al. 2004; Rendtorff et al. 2013; Ladsous et al. 2014; Pique et al. 2014). The variant was absent from 346 control chromosomes but is reported at a frequency of 0.00035 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Thr416Pro variant protein is retained in the endoplasmic reticulum and does not reach the plasma membrane as wild type, and the variant protein showed almost complete loss of iodide transport capacity (Rotman-Pikielny et al. 2002; Yoon et al. 2008). Based on the evidence the p.Thr416Pro 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.
Invitae RCV000435157 SCV000939229 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 416 of the SLC26A4 protein (p.Thr416Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs28939086, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Pendred syndrome (PMID: 24224479). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in individuals and families with Pendred syndrome (PMID: 14679580, 24224479, 9618166). ClinVar contains an entry for this variant (Variation ID: 4818). Experimental studies have shown that this missense change disrupts SLC26A4 protein activity (PMID: 12354788, 18310264, 10861298). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005087 SCV000025263 pathogenic Pendred syndrome 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000005087 SCV000040674 pathologic Pendred syndrome 2011-12-22 no assertion criteria provided curation Converted during submission to Pathogenic.

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