Submissions for variant NM_000441.2(SLC26A4):c.1195T>C (p.Ser399Pro)

gnomAD frequency: 0.00003  dbSNP: rs747431002

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000669625	SCV001323032	uncertain significance	Pendred syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001004635	SCV001323033	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001004635	SCV001806725	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000669625	SCV001806726	uncertain significance	Pendred syndrome	2021-07-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000669625	SCV002060311	uncertain significance	Pendred syndrome	2021-11-09	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.1195T>C(S399P) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. S399P has been observed in a case with relevant disease (PMID: 16283880). Functional assessments of this variant are available in the literature (PMID: 31599023). S399P has been observed in population frequency databases (gnomAD: SAS 0.09%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.1195T>C(S399P) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV002499166	SCV002784222	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-02-28	criteria provided, single submitter	clinical testing
Invitae	RCV002531233	SCV003519622	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 399 of the SLC26A4 protein (p.Ser399Pro). This variant is present in population databases (rs747431002, gnomAD 0.09%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 16283880). ClinVar contains an entry for this variant (Variation ID: 554065). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 31599023). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV002531233	SCV003921568	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in individuals with nonsyndromic hearing loss, and no second SLC26A4 variant was identified (Hutchin et al., 2005; Adhikary et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate impaired I-/Cl- antiport activities, but no effect on the HCO3-/Cl- antiport activities (Wasano et al., 2020); This variant is associated with the following publications: (PMID: 34426522, 26188157, 33199029, 35186384, 31599023, 16283880, 27771369)
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004635	SCV000994883	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment