SLC3A1 was first reported in relation to autosomal recessive cystinuria in 1994 (Calonge MJ, et al., PMID: 8054986). At least 236 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 11 probands in 6 publications (PMIDs: 8054986, 8792820, 16374432, 16138908, 9648062, 28049243). Variants in this gene segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the biochemical function of SLC3A1 in a cystine, ornithine, arginine, and lysine transporter protein complex (PMID: 8486766), its interaction with b(0,+)AT in that complex (PMID: 18332091), and its expression in the kidneys (PMID: 8486766), where the protein complex absorbs cystine, ornithine, arginine, and lysine back into the blood during urine formation. This gene-disease relationship is further supported by mouse and canine models which recapitulate the elevated urinary cystine, ornithine, arginine, and lysine levels associated with abnormal function of this protein, leading to formation of cystine crystals and stones in the bladder or kidneys. In summary, SLC3A1 is definitively associated with autosomal recessive cystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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