Submissions for variant NM_000341.4(SLC3A1):c.1354C>T (p.Arg452Trp)

gnomAD frequency: 0.00007  dbSNP: rs201502095

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000402894	SCV000430671	pathogenic	Cystinuria	2017-04-27	criteria provided, single submitter	clinical testing	The SLC3A1 c.1354C>T (p.Arg452Trp) variant has been reported in eight studies in which it is found in at least ten individuals with cystinuria, including three homozygotes, four compound heterozygotes, two heterozygotes in whom a second variant was not identified, and one heterozygote who carried a second heterozygous variant in the SLC7A9 gene (Endsley et al. 1997; Bisceglia et al. 2001; Guillen et al. 2004; Font-Llitjos et al. 2005; Skopkova et al. 2005; Brauers et al. 2006; Eggerman et al. 2011; Halbritter et al. 2012). The variant was absent from a total of 178 controls, but is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg452Trp variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000402894	SCV001403358	pathogenic	Cystinuria	2022-11-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 336205). This missense change has been observed in individual(s) with cystinuria (PMID: 9186880, 25296721, 30146843; Invitae). This variant is present in population databases (rs201502095, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 452 of the SLC3A1 protein (p.Arg452Trp).
Fulgent Genetics, Fulgent Genetics	RCV000402894	SCV002795958	pathogenic	Cystinuria	2021-12-16	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000402894	SCV003922393	pathogenic	Cystinuria		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000402894	SCV004027644	likely pathogenic	Cystinuria	2023-05-24	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5,PP3