Submissions for variant NM_000441.2(SLC26A4):c.1225C>T (p.Arg409Cys)

gnomAD frequency: 0.00002  dbSNP: rs147952620

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411132	SCV000486998	likely pathogenic	Pendred syndrome	2016-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV000811142	SCV000951393	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 409 of the SLC26A4 protein (p.Arg409Cys). This variant is present in population databases (rs147952620, gnomAD 0.007%). This missense change has been observed in individuals with non-syndromic enlargement of vestibular aqueduct and hearing loss (PMID: 18167283, 23185506, 25372295). ClinVar contains an entry for this variant (Variation ID: 371421). 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: 23185506). This variant disrupts the p.Arg408 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618166, 19786220, 24224479). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000770861	SCV002026887	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000411132	SCV002026898	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000770861	SCV004201896	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-08-08	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770861	SCV000902369	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000411132	SCV002079993	pathogenic	Pendred syndrome	2021-07-16	no assertion criteria provided	clinical testing