Submissions for variant NM_000441.2(SLC26A4):c.367C>T (p.Pro123Ser)

dbSNP: rs984967571

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469306	SCV002766035	likely pathogenic	Pendred syndrome	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.367C>T (p.Pro123Ser) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) 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 251418 control chromosomes (gnomAD). c.367C>T has been reported in the literature in homozygous- and compound heterozygous individuals affected with nonsyndromic hearing loss and Pendred Syndrome (Tsukamoto_2003, Miyagawa_2014, Ideura_2019, Nakano_2022). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased membrane localization and almost complete absence of transporter activity for the variant protein (Ishihara_2010, Wasano_2020). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic (n=1) or reported an affected individual (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001004620	SCV004201832	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-18	criteria provided, single submitter	clinical testing
Invitae	RCV003558616	SCV004294535	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 123 of the SLC26A4 protein (p.Pro123Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (PMID: 24599119, 31427586). ClinVar contains an entry for this variant (Variation ID: 691506). 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. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 20826203, 31599023, 32165640). For these reasons, this variant has been classified as Pathogenic.
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004620	SCV000994864	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment