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

gnomAD frequency: 0.00021  dbSNP: rs28939086

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://gnomad.broadinstitute.org/; 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	2022-02-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that presence of T416P is associated with decreased or absent pendrin-induced transport of chloride, iodide, and bicarbonate in Xenopus oocytes (Scott et al., 2000; Yoon et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22975760, 24224479, 19017801, 9618167, 18283249, 20301640, 12354788, 31599023, 18310264, 15531480, 26969326, 28000701, 23336812, 29739340, 30240412, 27771369, 30484383, 24860705, 31827275, 31980526, 32488467, 34426522, 34171171, 32387678, Byun[article], 31589614, 33199029, 35114279, 33583874, 33827324, 10861298, 11317356, 9618166)
Fulgent Genetics, Fulgent Genetics	RCV000036432	SCV000893731	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 416 of the SLC26A4 protein (p.Thr416Pro). This variant is present in population databases (rs28939086, gnomAD 0.04%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 9618166, 14679580, 24224479). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4818). 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: 10861298, 12354788, 18310264). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000005087	SCV001193963	pathogenic	Pendred syndrome	2019-11-18	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.1246A>C(T416P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 23336812, 9618166, 9618167, 12354788 and 18310264. Classification of NM_000441.1(SLC26A4):c.1246A>C(T416P) 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001004638	SCV001244767	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2018-07-03	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000441.1(SLC26A4):c.1246A>C, has been identified in exon 10 of 21 of the SLC26A4 gene. The variant is predicted to result in a minor amino acid change from threonine to proline at position 416 of the protein (NP_000432.1(SLC26A4):p.(Thr416Pro)). The threonine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the sulfate transporter domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.02% (55 heterozygotes in 276514, 0 homozygotes). The variant has been previously described as pathogenic (ClinVar, HGMD, Deafness variation database) and has been shown to segregate in multiple families with Pendred syndrome (Clinvar, Van Heuwe, P. et al. (1998)). It is one of the most commonly reported SLC26A4 variants associated with hearing loss in Europeans. Additionally, functional analysis has shown that the altered pendrin fails to localise to the cell membrane and is retained in the intracellular region (Yoon, JS. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	RCV001004638	SCV001809840	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000435157	SCV002020672	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001004638	SCV002027173	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005087	SCV002027184	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005087	SCV003934513	pathogenic	Pendred syndrome	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1246A>C (p.Thr416Pro) 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 0.0002 in 250802 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.1246A>C has been reported in the literature in multiple bi-allelic individuals affected with Pendred Syndrome (examples: Napiontek_2004 and Mey_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15531480, 31633822). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004638	SCV004201837	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-17	criteria provided, single submitter	clinical testing
OMIM	RCV000005087	SCV000025263	pathogenic	Pendred syndrome	2008-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000005087	SCV000040674	not provided	Pendred syndrome		no assertion provided	literature only
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004638	SCV000994888	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment
Natera, Inc.	RCV000005087	SCV001459922	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000435157	SCV001918467	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000435157	SCV001953957	pathogenic	not provided		no assertion criteria provided	clinical testing