ClinVar Miner

Submissions for variant NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn) (rs121434346)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002096 SCV000221212 pathogenic Neutral 1 amino acid transport defect 2014-04-24 criteria provided, single submitter clinical testing The p.Asp173Asn (NM_001003841.2 c.517G>A) variant in the SLC6A19 gene has been r eported at least 10 individuals with Hartnup disease, 2 of whom were homozygous and 8 of whom were compound heterozygous with another SLC6A19 variant (Seow 2004 , Azmanov 2008). This is the most frequent pathogenic variant in patients of Eur opean descent (Azmanov 2007). This variant has also been reported in ClinVar (V ariation ID#2019), as pathogenic or likely pathogenic by three laboratories. In vitro studies indicate this variant causes a partial inactivation of the protein (Seow 2004, Camargo 2009). The p.Asp173Asn variant has been identified in 0.3% (384/126,562) of European chromosomes by the Genome Aggregation Database (gnomAD ; http://gnomad.broadinstitute.org; dbSNP rs121434346), though this frequency is low enough to be consistent with a recessive carrier frequency. In summary, th is variant meets our criteria to be classified as pathogenic for Hartnup disease in an autosomal recessive manner based on functional studies and its occurrence in individuals with this disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000413766 SCV000336680 pathogenic not provided 2015-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000413766 SCV000491321 likely pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing The D173N likely pathogenic variant in the SLC6A19 gene has been reported previously in association with autosomal recessive Hartnup disease when present in the homozygous state or when in trans with another disease-causing pathogenic variant (Seow et al., 2004). Functional studies have shown the transport activity was reduced in the D173N construct compared to wild type (Seow et al, 2004; Camargo et al., 2009). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports that D173N was observed in 29/8600 alleles (0.34%) from individuals of European background, indicating it may be a rare variant in this population. The D173N variant is a semi-conservative amino acid substitution, which occurs in the extracellular domain at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function.
Genetic Services Laboratory, University of Chicago RCV000002096 SCV000597114 pathogenic Neutral 1 amino acid transport defect 2016-08-04 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000413766 SCV000610502 pathogenic not provided 2017-07-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763127 SCV000893679 pathogenic Hyperglycinuria; Neutral 1 amino acid transport defect; Iminoglycinuria 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV001170020 SCV001251694 uncertain significance not specified 2020-05-03 criteria provided, single submitter clinical testing
Invitae RCV000413766 SCV001584115 pathogenic not provided 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 173 of the SLC6A19 protein (p.Asp173Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs121434346, ExAC 0.3%). This variant has been reported to be homozygous or compound heterozygous with another SLC6A19 variant in many individuals affected with Hartnup disorder (PMID: 15286788, 17555458, 18484095, 21814048). This allele is the most common variant associated with Hartnup disorder reported in the literature. ClinVar contains an entry for this variant (Variation ID: 2019). Experimental studies have shown that this missense change decreases SLC6A19 activity (PMID: 15286788, 19185582). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002096 SCV000022254 pathogenic Neutral 1 amino acid transport defect 2004-09-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000413766 SCV001741933 pathogenic not provided no assertion criteria provided clinical testing

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