Submissions for variant NM_057176.3(BSND):c.35T>C (p.Ile12Thr)

gnomAD frequency: 0.00002  dbSNP: rs121908144

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214565	SCV001386250	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 12 of the BSND protein (p.Ile12Thr). This variant is present in population databases (rs121908144, gnomAD 0.02%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 19646679, 21541222). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4388). 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 BSND protein function. Experimental studies have shown that this missense change affects BSND function (PMID: 19646679). For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000785598	SCV002521666	pathogenic	Bartter disease type 4A	2022-05-22	criteria provided, single submitter	clinical testing	This variant was previously reported in trans with another pathogenic variant in this gene (PMID: 19646679) and co-segregated with Sensorineural deafness with mild renal dysfunction in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 19646679). In addition, it was observed in multiple affected individuals with a consistent phenotype from unrelated families (PMID: 19646679). Functional assays showed that the variant had strong level of impact on gene/protein function (PMID: 19646679). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.941>=0.6, 3CNET: 0.815>=0.75). A missense variant is a common mechanism associated with Sensorineural deafness with mild renal dysfunction. It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281695	SCV002572062	pathogenic	Bartter syndrome	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: BSND c.35T>C (p.Ile12Thr) results in a non-conservative amino acid change in 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 2e-05 in 251442 control chromosomes. c.35T>C has been reported in the literature as homozygous genotypes in individuals affected with non-syndromic deafness and as a compound heterozygous genotype with another loss of function variant, c.10G>T (p.E4*), in individuals with features of Bartter Syndrome, Type 4a (example, Riazuddin_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating intact chloride channel function and impaired chaperone function of the protein in intracellular trafficking (Riazuddin_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004638	SCV000024812	pathogenic	Sensorineural deafness with mild renal dysfunction	2009-08-01	no assertion criteria provided	literature only
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785598	SCV000924173	uncertain significance	Bartter disease type 4A		flagged submission	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291206	SCV001479631	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research