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

gnomAD frequency: 0.00004  dbSNP: rs111033220

Total submissions: 15

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.
Laboratory for Molecular Medicine, Mass General Brigham 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.
GeneDx	RCV000268093	SCV000329520	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	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); Published functional studies demonstrate 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); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16711435, 21961810, 24338212, 25266519, 19786220, 24224479, 23469187, 15747138, 25468468, 20842945, 26763877, 15811013, 19509082, 11919333, 24007330, 27771369, 30733538, 32165640, 17718863, 9618167, 16283880, 28444304, 28604962, 28964290, 29372807, 30622556, 30693673, 31035178, 30036422, 31599023, 30842343, 31914302, 31541171, 32417962, 30896630, 30275481, 11932316, 31589614, 32447495, 15905611, 32645618, 33597575)
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000515696	SCV000611814	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000036430	SCV000893730	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000268093	SCV000947125	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 410 of the SLC26A4 protein (p.Thr410Met). This variant is present in population databases (rs111033220, gnomAD 0.06%). This missense change has been observed in individuals with clinical features of Pendred syndrome (PMID: 9618167, 11919333, 11932316, 24224479, 25468468). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43498). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316, 24007330). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000576483	SCV001194244	pathogenic	Pendred syndrome	2019-12-24	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.1229C>T(T410M) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 16283880, 15355436, 11919333, 24224479, 21961810, 11932316, 19786220 and 9618167. Classification of NM_000441.1(SLC26A4):c.1229C>T(T410M) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576483	SCV001572470	pathogenic	Pendred syndrome	2021-04-09	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1229C>T (p.Thr410Met) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250840 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00018 vs 0.0035), allowing no conclusion about variant significance. c.1229C>T has been widely reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coyle_1998, Fugazzola_2002, Chen_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and one espert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000515696	SCV002756426	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000268093	SCV003917544	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	SLC26A4: PM3:Very Strong, PM2, PP1:Moderate
Baylor Genetics	RCV000515696	SCV004201840	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-14	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000515696	SCV000902359	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV000515696	SCV000994887	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
Natera, Inc.	RCV000576483	SCV001455811	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291347	SCV001479821	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research