Submissions for variant NM_000441.2(SLC26A4):c.589G>A (p.Gly197Arg)

dbSNP: rs111033380

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001056927	SCV001221394	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 197 of the SLC26A4 protein (p.Gly197Arg). This variant is present in population databases (rs111033380, gnomAD 0.006%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 17718863, 21961810, 23385134, 28576516). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43562). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553550	SCV001774439	pathogenic	Pendred syndrome	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.589G>A (p.Gly197Arg) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain 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 4e-06 in 251396 control chromosomes. c.589G>A has been reported in the literature in multiple individuals affected with SLC26A4-related conditions (e.g. Chai_2013, Luo_2020). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001553550	SCV002026620	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482978	SCV002793602	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-12-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000770858	SCV004201895	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-08-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036500	SCV000060155	likely pathogenic	Rare genetic deafness	2008-01-02	no assertion criteria provided	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770858	SCV000902364	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control