Submissions for variant NM_000341.4(SLC3A1):c.1750del (p.Arg584fs)

dbSNP: rs775827496

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000416445	SCV000494250	likely pathogenic	Cystinuria	2016-07-18	criteria provided, single submitter	clinical testing	The c.1750delA (p.Arg584Glufs*14) frameshift variant (also referred to as c.1749delA in the medical literature) in the SLC3A1 gene has been previously reported in several individuals who were diagnosed with cystinuria (Gasparini et al., 1995; Chillaron J et al., 2010). Additional frameshift variants that are further downstream (towards the 3’-end of the gene) have also been reported in affected individuals (Chillaron J et al., 2010). Although this variant is present in the last exon of the gene, the C-terminal tail of this protein that is predicted to be lost as a result of this variant contains cysteine residues that are critical for disulfide bond formation and biogenesis of the transporter (Rius M et al., 2016) .This variant is either absent in the population databases (Exome Sequencing Project, 1000 Genomes) or present at a frequency below that of the disease allele (<0.01%). Therefore, this collective evidence supports the classification of the c.1750delA (p.Arg584Glufs*14) as a Likely pathogenic variant for Cystinuria. We have confirmed this finding in our laboratory using Sanger sequencing.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000416445	SCV000967641	likely pathogenic	Cystinuria	2018-01-17	criteria provided, single submitter	clinical testing	The p.Arg584GlufsX14 (NM_000341.3 c.1750delA) variant in SLC3A1 (legacy nomencla ture c.1749delA) has been reported in at least 8 individuals with cystinuria, in cluding 1 confirmed compound heterozygote (Gasparini 1995, Font-Llitjos 2005, Ch illaron 2010, Gaildrat 2017). This variant has also been reported in ClinVar (Va riation ID#375410). While this variant occurs in the last exon and is expected n ot to undergo nonsense-mediated decay, in vitro functional studies have shown th e region downstream of this variant in SLC3A1 is essential for forming disulfide bonds and its absence may disrupt biogenesis (Rius 2012). Additionally, multipl e frameshift variants have been reported downstream of this position in patients with cystinuria, suggesting deletion of this region may have functional consequ ence. This variant has been identified in 7/111436 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs10 57519470), though this frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to full y establish its clinical significance, the p.Arg584GlufsX14 variant is likely pa thogenic for cystinuria in an autosomal recessive manner based upon observations in affected individuals, functional studies, and predicted impact to the protei n. ACMG/AMP Criteria applied: PM2, PM3, PVS1_Moderate, PS3_Supporting (Richards 2015).
Invitae	RCV000416445	SCV001588927	pathogenic	Cystinuria	2023-07-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg584Glufs*14) in the SLC3A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the SLC3A1 protein. This variant is present in population databases (rs775827496, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cystinuria (PMID: 7573036). This variant is also known as 1749delA. ClinVar contains an entry for this variant (Variation ID: 375410). This variant disrupts a region of the SLC3A1 protein in which other variant(s) (p.Glu585Alafs*24) have been determined to be pathogenic (PMID: 11748844, 25964309, 28717662; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.