Submissions for variant NM_001003841.3(SLC6A19):c.532C>T (p.Arg178Ter)

gnomAD frequency: 0.00031  dbSNP: rs147837686

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174897	SCV001338321	pathogenic	Neutral 1 amino acid transport defect	2020-02-20	criteria provided, single submitter	clinical testing	Variant summary: SLC6A19 c.532C>T (p.Arg178X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.5e-05 in 251854 control chromosomes (gnomAD). c.532C>T has been reported in the literature in individuals affected with Hartnup disorder (e.g. Azmanov_2008, Kuster_2018). These data indicate that the variant may be associated with disease. In functional analysis using Xenopus leavis oocytes, the variant was found to have impaired leucine uptake (Azmanov_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001536072	SCV001752769	pathogenic	Hyperglycinuria; Neutral 1 amino acid transport defect; Iminoglycinuria	2021-06-30	criteria provided, single submitter	clinical testing
DASA	RCV001174897	SCV002061223	pathogenic	Neutral 1 amino acid transport defect	2022-01-05	criteria provided, single submitter	clinical testing	The c.532C>T;p.(Arg178*) variant creates a premature translational stop signal in the SLC6A19 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 917714; PMID: 18484095; 19472175) - PS4_supporting. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 18484095) - PS3_supporting. The variant is present at low allele frequencies population databases (rs147837686 – gnomAD 0.02827%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Invitae	RCV001873654	SCV002245880	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 917714). This premature translational stop signal has been observed in individual(s) with Hartnup disorder (PMID: 18484095). This variant is present in population databases (rs147837686, gnomAD 0.04%). This sequence change creates a premature translational stop signal (p.Arg178*) in the SLC6A19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A19 are known to be pathogenic (PMID: 15286787, 15286788).
PreventionGenetics, part of Exact Sciences	RCV003413970	SCV004115612	pathogenic	SLC6A19-related condition	2023-03-29	criteria provided, single submitter	clinical testing	The SLC6A19 c.532C>T variant is predicted to result in premature protein termination (p.Arg178*). This variant was reported in an individual with Hartnup disorder (Azmanov et al. 2008. PubMed ID: 18484095; Bröer. 2009. PubMed ID: 19472175). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1212468-C-T). Nonsense variants in SLC6A19 are expected to be pathogenic. This variant is interpreted as pathogenic.