Submissions for variant NM_000441.2(SLC26A4):c.1226G>A (p.Arg409His)

gnomAD frequency: 0.00006  dbSNP: rs111033305

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036428	SCV000060083	pathogenic	Rare genetic deafness	2015-08-26	criteria provided, single submitter	clinical testing	The p.Arg409His variant in SLC26A4 has been identified in >20 individuals with h earing loss and EVA and/or goiter who were homozygous or compound heterozygous w ith a disease-causing variant on the remaining allele. In addition, the p.Arg40 9His variant segregated with disease in at least three affected siblings (Blons 2004, Chai 2013, Fugazzola 2007, Pera 2008, Pera 2008, Rendtorff 2013, Van Hauwe 1998, LMM data). This variant has been identified in 13/66658 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033305); however, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 hearing loss or Pendred syndrome in an autos omal recessive manner based on multiple co-occurrences with pathogenic SLC26A4 v ariants in individuals with hearing loss.
GeneDx	RCV000424441	SCV000514663	pathogenic	not provided	2020-06-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to reduction of pendrin-induced iodide and chloride transport (Gillam et al., 2005; Pera et al., 2008; Wasano et al., 2020); 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: 27247933, 21154317, 19017801, 16053392, 24348793, 23273637, 26226137, 22717225, 19608655, 25266519, 19786220, 9618166, 11919333, 27771369, 28964290, 30760291, 31599023, 21961810, 16570074, 24224479, 26100058, 20597900, 31541171, 31827275, 30896630, 32425884, 30275481, 31589614, 32447495, 32860223)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506765	SCV000605150	pathogenic	not specified	2017-03-02	criteria provided, single submitter	clinical testing
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000515653	SCV000611813	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000424441	SCV000936543	pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 409 of the SLC26A4 protein (p.Arg409His). This variant is present in population databases (rs111033305, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness or Pendred syndrome (PMID: 11919333, 16053392, 19786220, 20597900, 21961810, 24224479, 26100058, 26226137). 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: 43496). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 16053392). This variant disrupts the p.Arg409 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18167283, 23185506, 25372295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000169222	SCV001194157	pathogenic	Pendred syndrome	2020-01-06	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.1226G>A(R409H) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 17718863, 17443271, 15355436, 18813951, 11919333, 19786220, 16053392, 21961810, 24224479 and 19017801. Classification of NM_000441.1(SLC26A4):c.1226G>A(R409H) 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	RCV000515653	SCV001244766	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2018-04-09	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000441.1(SLC26A4):c.1226G>A, 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 arginine to histidine at position 409 of the protein (NP_000432.1(SLC26A4):p.(Arg409His)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the sulfate permease superfamily. 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 0.009% (0 homozygotes). The variant has been previously described as pathogenic multiple times (Kahrizi K. et al. (2009), Blons H. et al. (2004); Bogazzi F. et al. (2014), Chai Y. et al. (2013)). It has also been shown to segregate with the disease in at least 1 family (Fugazzola L. et al. 2007). Additionally, it has been shown that the mutation impairs pendrin (an anion exhange protein) function. Functional studies demonstrate that mutants lose the ability to mediate iodide efflux (Gillaim M. et al. 2005). Three different variants in the same codon resulting in a change to cysteine, proline and leucine have also been shown to cause Pendred syndrome and enlarged vestibular aqueduct (ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814024	SCV001755270	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	RCV000169222	SCV001792218	pathogenic	Pendred syndrome		criteria provided, single submitter	research	in homozygosis in two siblings with bilateralnon-syndromic sensorineural prelingual hearing loss (familial)
Revvity Omics, Revvity	RCV000424441	SCV002020684	pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000515653	SCV002026909	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169222	SCV002026919	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496559	SCV002810525	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000169222	SCV003935253	likely pathogenic	Pendred syndrome	2020-05-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169222	SCV004020619	pathogenic	Pendred syndrome	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1226G>A (p.Arg409His) 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 0.0001 in 250826 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0001 vs 0.0035), allowing no conclusion about variant significance. c.1226G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Pendred Syndrome and individuals with bilateral non-syndromic hearing loss, both with and without enlarged vestibular aqueduct (e.g. Fugazzola_2007, Chai_2013). 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: 23918157, 17766716). Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000515653	SCV004201802	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000424441	SCV005413792	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_strong, PS3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002496559	SCV005416677	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP3
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000515653	SCV000902370	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	RCV000515653	SCV000994885	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	RCV000169222	SCV001438735	pathogenic	Pendred syndrome	2020-05-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169222	SCV001455810	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291345	SCV001479819	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000515653	SCV004099388	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-30	no assertion criteria provided	clinical testing