ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1229C>T (p.Thr410Met) (rs111033220)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000576483 SCV000840510 pathogenic Pendred syndrome 2018-09-17 reviewed by expert panel curation This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 25372295, 23638949, 25468468, 24338212, 25394566, 19786220, 19017801, 27541434, 21366435, 17309986, 24007330, 24224479, 21961810, 2844304, 19509082, 15811013). The p.Thr410Met variant in SLC26A4 has been reported to segregate in an autosomal recessive pattern with hearing loss in at least 7 family members (PP1_Strong; PMID: 19017801, 9618167, 15811013). Computational prediction tools and conservation analysis suggest that the p.Thr410Met variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA or Mondini malformation (PP4; PMID: 15355436, 15811013). The allele frequency of the p.Thr410Met variant in the SLC26A4 gene is 0.062% (19/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PP1_S, PP3, PS3_P, PM2_P, PP4.
Counsyl RCV000576483 SCV000677971 pathogenic Pendred syndrome 2017-06-16 criteria provided, single submitter clinical testing
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000515696 SCV000611814 pathogenic Enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036430 SCV000893730 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000268093 SCV000329520 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The T410M variant in the SLC26A4 gene has been reported in both the homozygous and compound heterozygous state in multiple individuals with Pendred syndrome (Coyle et al., 1998; Arellano et al., 2005; Wang et al., 2007; Dai et al., 2009). T410M accounted for 4% of the SLC26A4 variants identified in a cohort of Korean patients with hearing loss and enlarged vestibular aqueduct (Lee et al., 2014). In vitro functional studies indicate this variant results in reduced or absent surface expression of the protein and impairs anion exchange activity (Lee et al., 2014; Taylor et al., 2002). The T410M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T410M as a pathogenic variant.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515696 SCV000902359 likely pathogenic Enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
Invitae RCV000268093 SCV000947125 pathogenic not provided 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 410 of the SLC26A4 protein (p.Thr410Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs111033220, ExAC 0.06%). This variant has been observed to segregate with clinical features of Pendred syndrome in a family (PMID: 11919333). It has also been identified in several individuals with clinical features of Pendred syndrome (PMID: 11919333, 9618167, 25468468, 24224479, 11932316). ClinVar contains an entry for this variant (Variation ID: 43498). This variant has been reported to affect SLC26A4 protein function (PMID:24007330, 11932316). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824770 SCV000060085 pathogenic Rare genetic deafness 2012-03-22 criteria provided, single submitter clinical testing The Thr410Met variant in SLC26A4 has been reported in over 34 individuals with h earing loss and was not identified in 1576 control chromosomes (Arellano 2005, D ai 2009, Hutchin 2005, Wang 2007). Many of these individuals were homozygous or compound heterozygous. This variant causes the protein to be retained in the en doplasmic reticulum instead of functioning normally at the plasma membrane, thus greatly reducing its sodium-iodide efflux action (Taylor 2002). In summary, thi s variant meets our criteria to be classified as pathogenic.

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