Submissions for variant NM_000441.2(SLC26A4):c.1489G>A (p.Gly497Ser)

gnomAD frequency: 0.00006  dbSNP: rs111033308

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036444	SCV000060099	pathogenic	Rare genetic deafness	2011-12-23	criteria provided, single submitter	clinical testing	The Gly497Ser variant in SLC26A4 has been reported in six probands with Pendred syndrome or sensorineural hearing loss (Scott 2000, Bogazzi 2004, Gardner 2006, Jiang 2010, Li 1998, Pera 2008, Prasad 2004, Yoon 2008). Four of these probands were homozygous or compound heterozygous. Functional studies have shown that the Gly487Ser variant inhibits protein function (Scott 2000, Yoon 2008). In summary , this variant meets our criteria to be classified as pathogenic.
GeneDx	RCV000489866	SCV000577405	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to abolishment of complex glycosylation and significant reduction of ion transport activities (Scott et al., 2000; Yoon et al., 2008; Wasano et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 34680964, 10861298, 18310264, 27771369, 28964290, 30139988, 31387071, 31599023, 9500541, 26763877, 29546359, 30275481, 34426522, 32747562, 31589614, 33152970, 32645618)
Invitae	RCV000489866	SCV001215510	pathogenic	not provided	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 497 of the SLC26A4 protein (p.Gly497Ser). This variant is present in population databases (rs111033308, gnomAD 0.005%). This missense change has been observed in individuals with sensorineural hearing loss and enlarged vestibular aqueduct (PMID: 9500541, 26763877, 28964290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43510). 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, 18310264). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000489866	SCV001250493	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375472	SCV001572145	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PP3_Supporting
Genome-Nilou Lab	RCV001004645	SCV002027240	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169242	SCV002027251	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001004645	SCV002059889	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-08-01	criteria provided, single submitter	research	SLC26A4 c.1489G>A, p.G497S alters a residue of SLC26A4 that is previously shown to damage protein function. The variant is homozygous in 3 Palestinian children with pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and is present in 7/282774 alleles on gnomAD, all heterozygotes.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169242	SCV002500597	pathogenic	Pendred syndrome	2022-03-23	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1489G>A (p.Gly497Ser) results in a non-conservative amino acid change in 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 2e-05 in 251406 control chromosomes. c.1489G>A has been reported in the literature in multiple individuals affected with sensorineural hearing loss and enlarged vestibular aqueduct, and the variant segregated with disease in affected families (examples: Li_1998, Yazdanpanahi_2015, Abu Rayyan_2020). In functional studies the variant was reported to result in a low level of of pendrin activity (Scott_2000). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, seven classified as pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000489866	SCV003821141	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001004645	SCV003921993	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-05-07	criteria provided, single submitter	clinical testing	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). While the p.(Gly497Ser) variant is typically reported in the context of deafness with enlarged vestibular aqueduct (MIM#600791), it cannot be ruled out that individuals with this variant will develop thyroid dysfunction in the future. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with hearing loss in a homozygous or compound heterozygous state (ClinVar, PMID:28964290, 9500541, 26763877). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV001004645	SCV004201843	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000169242	SCV000220517	pathogenic	Pendred syndrome	2018-02-21	no assertion criteria provided	clinical testing
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004645	SCV000994895	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
Natera, Inc.	RCV000169242	SCV001459928	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing