ClinVar Miner

Submissions for variant NM_057176.3(BSND):c.139G>A (p.Gly47Arg) (rs74315289)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000004637 SCV000914415 pathogenic Bartter disease type 4a 2018-09-17 criteria provided, single submitter clinical testing Across a selection of literature, the BSND c.139G>A (p.Gly47Arg) missense variant has been reported in at least six studies in which it is found in at least twelve individuals from seven families with Bartter syndrome including in eleven in a homozygous state and in one in a compound heterozygous state (Miyamura et al. 2003; Garcia-Nieto et al. 2006; Kitanaka et al. 2006; Brum et al. 2007; Park et al. 2011; Heilberg et al. 2015). The p.Gly47Arg variant was also found in a heterozygous state in at least six unaffected relatives (Garcia-Nieto et al. 2006; Park et al. 2011). The p.Gly47Arg variant was absent from control 100 healthy subjects and is reported at a frequency of 0.000289 in the total population of the Exome Sequencing Project. Expression in Xenopus oocytes demonstrated that the p.Gly47Arg abolished the stimulatory effect on chloride channels (Estevez et al. 2001). The p.Gly47Arg variant demonstrated reduced binding to CIC-K channels when expressed in MDCKII cells (Janssen et al. 2009). These results are consistent with the generally mild phenotype of individuals carrying the p.Gly47Arg variant. Based on the collective evidence, the p.Gly47Arg variant is classified as pathogenic for Bartter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000004637 SCV001135294 pathogenic Bartter disease type 4a 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001058739 SCV001223330 pathogenic not provided 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 47 of the BSND protein (p.Gly47Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs74315289, ExAC 0.03%). This variant has been observed to be homozygous or in combination with another BSND variant in individuals affected with Bartter syndrome (PMID: 12574213, 16328537, 21865213, 26537508), and has been shown to segregate with disease in families (PMID: 16572343). ClinVar contains an entry for this variant (Variation ID: 4387). This variant has been reported to affect BSND protein function (PMID: 11734858, 18776122). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000004637 SCV001571457 pathogenic Bartter disease type 4a 2020-12-01 criteria provided, single submitter research The BSND c.139G>A (p.Gly47Arg) missense variant alters a single amino acid in exon 1 of 4 of the encoded protein. This variant has been previously reported in the homozygous state in five individuals from two families who were affected with early onset Bartter syndrome and bilateral sensorineural hearing loss (PMID: 16572343). This variant has also been observed in the homozygous state in two individuals with congenital hearing loss and a mild clinical presentation of adult-onset Bartter syndrome (PMID: 12574213; 26537508). Additionally, this variant has been found in the compound heterozygous state with a loss-of-function nonsense variant in an individual with congenital hearing loss and early onset Bartter syndrome that required renal transplantation (PMID: 16328537). Functional studies show the p.Gly47Arg variant impairs ClC-K chloride channel activity (PMID: 11734858; 18776122). This variant is observed in the human population Genome Aggregation Database (gnomAD) with a minor allele frequency of 0.01% (25/250,814 alleles, 0 homozygotes) in all populations. In summary, the BSND p.Gly47Arg variant is considered pathogenic.
GeneDx RCV001058739 SCV001784557 pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing Published functional studies demonstrate that the G47R variant disrupts normal protein function (Estevez et al., 2001; Janssen et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 11734858, 31667618, 16572343, 21865213, 21158220, 16935888, 12574213, 26537508, 16328537, 18776122, 21269598)
Nilou-Genome Lab RCV000004637 SCV001810228 pathogenic Bartter disease type 4a 2021-07-22 criteria provided, single submitter clinical testing
OMIM RCV000004637 SCV000024811 pathogenic Bartter disease type 4a 2003-02-01 no assertion criteria provided literature only
PerkinElmer Genomics RCV000004637 SCV002017995 pathogenic Bartter disease type 4a 2021-06-16 no assertion criteria provided clinical testing

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