Submissions for variant NM_000441.2(SLC26A4):c.85G>C (p.Glu29Gln)

gnomAD frequency: 0.00011  dbSNP: rs111033205

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036509	SCV000060164	pathogenic	Rare genetic deafness	2015-09-14	criteria provided, single submitter	clinical testing	The p.Glu29Gln variant in SLC26A4 has been identified in multiple individuals wi th hearing loss and temporal bone abnormalities including over 15 probands who w ere compound heterozygous with another pathogenic variant in SLC26A4, and it has segregated in three affected siblings (Albert 2006, Campbell 2001, Gardner 2006 , Ladsous 2014, Pera 2008, Pourova 2010, Rendtorff 2013, LMM unpublished data). Functional studies have demonstrated that this variant impacts the protein func tion (Pera 2008). In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 nonsyndromic hearing loss or Pendred syndrome in an auto somal recessive manner.
Illumina Laboratory Services, Illumina	RCV004528081	SCV000915189	pathogenic	SLC26A4-related disorder	2018-11-24	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the SLC26A4 c.85G>C (p.Glu29Gln) missense variant has been reported in at least nine studies in which it was identified in a total of 18 individuals, including in a compound heterozygous state in 14 individuals, in a heterozygous state in three individuals, in a double heterozygous state in one individual and in one individual with unknown zygosity. Affected individuals were diagnosed with either Pendred syndrome, an autosomal recessive form of deafness, or enlarged vestibular aqueduct or Mondini dysplasia (Campbell et al. 2001; Prasad et al. 2004; Blons et al. 2004; Alberts et al. 2006; Yang et al. 2007; Pera et al. 2008; Pourova et al. 2010; Rendtorff et al. 2013; Ladous et al. 2014). The p.Glu29Gln variant was found to segregate in at least one study (Yang et al. 2007). The variant was absent from 469 controls and is reported at a frequency of 0.000229 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using fluorimetric measurements showed that the p.Glu29Gln variant protein has reduced chloride/iodide transport (Pera et al. 2008). Based on the collective evidence, the p.Glu29Gln 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	RCV001040420	SCV001203995	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 29 of the SLC26A4 protein (p.Glu29Gln). This variant is present in population databases (rs111033205, gnomAD 0.03%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 11317356, 15355436, 16570074, 20597900, 25394566). ClinVar contains an entry for this variant (Variation ID: 4839). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19017801). This variant disrupts the p.Glu29 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 22285650, 25372295), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001040420	SCV001249281	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001040420	SCV001779676	pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to reduced iodide transport activity (PMID: 19017801); This variant is associated with the following publications: (PMID: 14679580, 29372807, 24224479, 17503324, 16950989, 18285825, 15099345, 15355436, 16570074, 20597900, 23336812, 31589614, 34426522, 34170635, 33199029, 31541171, 36499699, 11317356, 19017801, 36555390, 36833263, 25394566)
Revvity Omics, Revvity	RCV001040420	SCV002023544	likely pathogenic	not provided	2020-12-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005111	SCV002026487	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169251	SCV002026498	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000005111	SCV002579551	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-03-15	criteria provided, single submitter	clinical testing
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000005111	SCV002756449	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496264	SCV002806806	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-08-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005111	SCV004201815	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001040420	SCV004225730	pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	PM2_supporting, PM3_very_strong, PS3_supporting
OMIM	RCV000005111	SCV000025287	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2008-08-01	no assertion criteria provided	literature only
Counsyl	RCV000169251	SCV000220535	pathogenic	Pendred syndrome	2019-06-09	no assertion criteria provided	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656195	SCV000678389	likely pathogenic	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000005111	SCV000902384	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000169251	SCV001455791	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001040420	SCV001952914	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001040420	SCV001966500	pathogenic	not provided		no assertion criteria provided	clinical testing