Submissions for variant NM_000441.2(SLC26A4):c.2162C>T (p.Thr721Met)

gnomAD frequency: 0.00003  dbSNP: rs121908363

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154350	SCV000204013	pathogenic	Rare genetic deafness	2016-03-29	criteria provided, single submitter	clinical testing	The p.Thr721Met variant in SLC26A4 has been reported in at least 7 individuals f rom 5 families with hearing loss and enlarged vestibular aqueduct (EVA) or Pendr ed Syndrome (Chen 2011, Ishihara 2010, Kahrizi 2009, Lopez-Bigas 2001, Usami 199 9). Individuals were either homozygous (2 families) or heterozygous with anoth er pathogenic variant (3 families). Compound heterozygous variants were confir med to be in trans in at least one family. In addition, a study showed that the Thr721Met variant impacts protein function (Ishihara 2010). This variant has b een identified in 5/11486 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908363); however, this freque ncy is low enough to be consistent with a recessive carrier frequency. In summa ry, this variant meets our criteria to be classified as pathogenic for autosomal recessive hearing loss with EVA or Pendred syndrome.
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000005096	SCV000611823	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057908	SCV001222431	pathogenic	not provided	2024-03-26	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 721 of the SLC26A4 protein (p.Thr721Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with enlarged vestibular aqueduct and hearing loss (PMID: 10190331, 26763877, 28964290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4826). 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: 20826203). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001057908	SCV001774332	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; variant protein is retained in the cytoplasm leading to the loss of normal anion transporter activity (Ishihara et al., 2010); This variant is associated with the following publications: (PMID: 15905611, 32447495, 31589614, 30275481, 31541171, 31599023, 31427586, 12112665, 18813951, 26763877, 24599119, 20826203, 23185506, 17949297, 11748854, 15355436, 21704276, 27176802, 20597900, 29871341, 28964290, 10190331, 12676893, 26004784, 14508505, 25266519, 17443271)
Revvity Omics, Revvity	RCV001057908	SCV002020671	pathogenic	not provided	2019-08-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005096	SCV002026970	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005097	SCV002026971	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005096	SCV004201835	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-01-19	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005096	SCV005399902	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-10-09	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 deafness, autosomal recessive 4, with enlarged vestibular aqueduct (MIM#600791) and 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 threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 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 STAS domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005041983	SCV005673665	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-05-24	criteria provided, single submitter	clinical testing
OMIM	RCV000005096	SCV000025272	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2003-12-01	no assertion criteria provided	literature only
OMIM	RCV000005097	SCV000025273	pathogenic	Pendred syndrome	2003-12-01	no assertion criteria provided	literature only
Counsyl	RCV000005097	SCV000221106	pathogenic	Pendred syndrome	2016-05-24	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000005096	SCV000902361	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	RCV000005096	SCV000994908	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
Natera, Inc.	RCV000005097	SCV001459940	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing