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

gnomAD frequency: 0.00168  dbSNP: rs121434346

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Eurofins Ntd Llc (ga)	RCV000413766	SCV000336680	pathogenic	not provided	2015-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000413766	SCV000491321	pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	Published functional studies have shown the SLC6A19 transport activity was reduced in the D173N construct compared to wild type (PMID: 19185582, 15286788); This variant is associated with the following publications: (PMID: 28787443, 15286788, 17555458, 25082825, 29431110, 30665703, 30487145, 31908951, 31980526, 34041853, 33848968, 31589614, 34426522, 18484095, 34297361, 19185582)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413766	SCV001584115	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 173 of the SLC6A19 protein (p.Asp173Asn). This variant is present in population databases (rs121434346, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Hartnup disorder (PMID: 15286788, 17555458, 18484095, 21814048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2019). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC6A19 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC6A19 function (PMID: 15286788, 19185582). For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000413766	SCV002011262	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000002096	SCV002023579	pathogenic	Neutral 1 amino acid transport defect	2023-12-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002096	SCV004803757	pathogenic	Neutral 1 amino acid transport defect	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: SLC6A19 c.517G>A (p.Asp173Asn) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 250978 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. c.517G>A has been reported in the literature in multiple individuals affected with Hartnup Disease (Seow_2004, Schuermans_2022), including those that were compound heterozygous with other pathogenic variants. 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, finding that the variant resulted in <50% of wild type leucine transport activity (Seow_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15286788, 35606766). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=10), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413766	SCV005413681	pathogenic	not provided	2024-07-10	criteria provided, single submitter	clinical testing	PP1_moderate, PM3_very_strong, PS3_supporting
Fulgent Genetics, Fulgent Genetics	RCV000002096	SCV005672141	pathogenic	Neutral 1 amino acid transport defect	2024-05-13	criteria provided, single submitter	clinical testing
OMIM	RCV000002096	SCV000022254	pathogenic	Neutral 1 amino acid transport defect	2004-09-01	no assertion criteria provided	literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001170020	SCV001251694	uncertain significance	not specified	2020-05-03	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000413766	SCV001741933	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413766	SCV001927875	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413766	SCV001971603	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415626	SCV004114770	pathogenic	SLC6A19-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The SLC6A19 c.517G>A variant is predicted to result in the amino acid substitution p.Asp173Asn. This variant has been reported in individuals with autosomal recessive Hartnup disorder and results in reduced transport activity compared to wild type (Seow et al. 2004. PubMed ID: 15286788; Camargo et al. 2009. PubMed ID: 19185582). This variant is reported in 0.30% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.