Submissions for variant NM_000441.2(SLC26A4):c.416G>T (p.Gly139Val)

dbSNP: rs756272252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378586	SCV001576188	pathogenic	not provided	2022-08-20	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs756272252, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the SLC26A4 protein (p.Gly139Val). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 19287372, 23918157, 25317404, 31700827). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly139 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 9618166), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 996638).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824946	SCV002074331	likely pathogenic	Pendred syndrome	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.416G>T (p.Gly139Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547; also described as the third transmembrane domain of Pendrin in Reiisi_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site and two predict the variant weakens this site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.9e-05 in 257564 control chromosomes (gnomAD and publication data). c.416G>T has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss (Anwar_2009, Yan_2013, Chai_2013, Reiisi_2014, Koohiyan_2021, Wu_2022) and this variant co-segregated with the disease in at least two families (Anwar_2009, Reiisi_2014). These data indicate that the variant is likely to be associated with disease. Additionally, missense variants in the same residue (G139A and G139E) have been reported in patients with Pendred syndrome in the Human Gene Mutation Database (e.g. Liu_2020, PMID: 9618166), supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23918157, 28941661, 19287372, 27771369, 31971949, 31700827, 32447495, 26683941, 26100058, 25317404, 30303587, 23296490, 33614372, 35982127). ClinVar contains an entry for this variant (Variation ID: 996638). Based on the evidence outlined above, the variant was classified as likely pathogenic.
3billion	RCV002051933	SCV002318847	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (ClinVar ID: VCV000996638, PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23918157). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:32447495,9618166). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.985>=0.6, 3CNET: 0.984>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV002051933	SCV004201937	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-05-09	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291245	SCV001479670	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Natera, Inc.	RCV001824946	SCV002079969	likely pathogenic	Pendred syndrome	2021-05-04	no assertion criteria provided	clinical testing