Submissions for variant NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro)

gnomAD frequency: 0.00035  dbSNP: rs80338848

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824766	SCV000060160	pathogenic	Rare genetic deafness	2017-05-04	criteria provided, single submitter	clinical testing	The p.Leu236Pro variant in SLC26A4 has been reported in at least 15 individuals with either nonsyndromic hearing loss or Pendred syndrome who were homozygous or compound heterozygous, and it segregated in 4 affected family members from 2 fa milies (Busi 2012, Pryor 2005, Pourova 2010, Siem 2010, Van Hauwe 1998, LMM data ). One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002). The p.Leu236Pr o variant has been identified in 0.1% (78/126638) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 80338848). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on bi-allelic occurrences in multiple affected indi viduals, segregation studies, functional evidence, and low frequency in the gene ral population. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Sup porting.
Eurofins Ntd Llc (ga)	RCV000524013	SCV000331545	pathogenic	not provided	2017-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000524013	SCV000616878	pathogenic	not provided	2020-05-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to improper intracellular localization of pendrin and loss of pendrin-induced iodide and chloride transport (Scott et al., 2000; Yoon et al., 2008); Common variant in Caucasian populations, accounting for approximately 10% of pathogenic alleles in published studies of Western European individuals (Tsukada et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 26969326, 11317356, 31827275, 12354788, 10861298, 18310264, 9618166, 26022370, 10700480, 20553101, 9618167, 22717225, 27771369, 31163360, 15689455, 20597900, 25999548, 31980526, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000036505	SCV000893725	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528073	SCV000916169	pathogenic	SLC26A4-related disorder	2018-09-21	criteria provided, single submitter	clinical testing	The SLC26A4 c.707T>C (p.Leu236Pro) missense variant is well described in the literature and is one of the three most common pathogenic variants in SLC26A4, which together account for 50% of the disease-causing alleles in probands with Pendred syndrome of northern European descent (Alasti et al. 2014; Tsukada et al. 2015). Across a selection of available literature, the p.Leu236Pro variant has been reported in at least four individuals in a homozygous state, 13 individuals in a compound heterozygous state, and one individual in a heterozygous state, all affected with Pendred syndrome (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001). The variant has also been reported in individuals affected with hearing loss, including two in a compound heterozygous state and five in a heterozygous state (Yan et al. 2017). Campbell et al. (2001) demonstrated segregation with disease in at least one multiplex family with temporal bone abnormalities. Haplotype analysis suggests a common founder effect for this variant (van Hauwe et al. 2008; Coyle et al. 1998). The p.Leu236Pro variant was absent from 257 control individuals (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Yan et al. 2017) and is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. Functional studies by Rotman-Pikielny et al. (2002) demonstrated that the variant protein is retained in the endoplasmic reticulum (ER) whereas the wild type protein targets to the plasma membrane. Yoon et al. (2008) confirmed the initial localization of the p.Leu236Pro variant protein in the ER and showed that after time, the protein was concentrated at the centrosome. They further determined that Cl-/HCO3- ion exchange activity of the variant protein was notably decreased, and that the variant was not temperature sensitive. Based on collective evidence, the p.Leu236Pro 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524013	SCV000958105	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the SLC26A4 protein (p.Leu236Pro). This variant is present in population databases (rs80338848, gnomAD 0.06%). This missense change has been observed in individual(s) with Pendred syndrome and hearing loss (PMID: 9618166, 15689455, 20553101, 20597900, 26969326). 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: 4817). 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000005086	SCV000993593	pathogenic	Pendred syndrome	2018-10-22	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000005086	SCV001193872	pathogenic	Pendred syndrome	2019-11-12	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.707T>C(L236P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 9618167, 9618166, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.707T>C(L236P) 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	RCV000005086	SCV001244769	pathogenic	Pendred syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 83 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sulfate permease family (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants in individuals with European descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000524013	SCV001250491	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375179	SCV001571785	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Supporting, BP4_Supporting
Revvity Omics, Revvity	RCV000524013	SCV002020683	pathogenic	not provided	2019-12-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001089560	SCV002026653	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005086	SCV002026664	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001089560	SCV004201834	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-27	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV000524013	SCV005328459	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing
OMIM	RCV000005086	SCV000025262	pathogenic	Pendred syndrome	2008-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000005086	SCV000040675	not provided	Pendred syndrome		no assertion provided	literature only
Natera, Inc.	RCV000005086	SCV001455801	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000524013	SCV001551437	pathogenic	not provided		no assertion criteria provided	clinical testing	The SLC26A4 p.L236P variant has been reported in multiple homozygous or compound heterozygous individuals with hearing loss or hearing impairment (Yan_2017_PMID:28273078; Tang_2015_PMID:25991456; Pryor_2005_PMID:15689455; Pourova_2010_PMID:20597900; Busi_2012_PMID:22717225; Campbell_2001_PMID:11317356; Siem_2010_PMID:20553101; Van Hauwe_1998_PMID:9618166). The variant was identified in dbSNP (ID: rs80338848) and ClinVar (classified as pathogenic by Invitae, GeneDx, EGL Genetic Diagnostics and nine other submitters). The variant was identified in control databases in 83 of 282766 chromosomes (0 homozygous) at a frequency of 0.0002935, and was observed at the highest frequency in the European (non-Finnish) population in 77 of 129104 chromosomes (freq: 0.0005964) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L236 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies have shown that this variant causes protein mislocalization and impaired iodide/chloride transport activity compared to wild type (Scott_2000_PMID:10861298, Rotman-Pikielny_2002_PMID:12354788, Yoon_2008_PMID:18310264). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000524013	SCV001955818	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000524013	SCV001969075	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528073	SCV004766575	pathogenic	SLC26A4-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The SLC26A4 c.707T>C variant is predicted to result in the amino acid substitution p.Leu236Pro. This variant has been reported to be causative for Pendred syndrome (van Hauwe et al 1998. PubMed ID: 9618166; Campbell et al 2001. PubMed ID: 11317356; Pourová et al 2010. PubMed ID: 20597900). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.