Submissions for variant NM_000441.2(SLC26A4):c.1667A>G (p.Tyr556Cys)

gnomAD frequency: 0.00002  dbSNP: rs763006761

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000515668	SCV000611819	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000670962	SCV000795889	likely pathogenic	Pendred syndrome	2017-11-21	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731741	SCV001984736	likely pathogenic	not specified	2019-12-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000515668	SCV002026955	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670962	SCV002026956	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV001851413	SCV002242931	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 556 of the SLC26A4 protein (p.Tyr556Cys). This variant is present in population databases (rs763006761, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness and/or Pendred syndrome (PMID: 9618167, 27573290, 28281779). ClinVar contains an entry for this variant (Variation ID: 446456). 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: 11932316, 31599023). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000515668	SCV004201900	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-08-01	criteria provided, single submitter	clinical testing
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV000515668	SCV000994899	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment