The relationship between SLC7A7 and Lysinuric Protein Intolerance (Autosomal Recessive) was evaluated using the ClinGen Clinical Validity Framework as of 10/17/19. Variants in SLC7A7 were first reported in humans with this disease as early as 1999 (Torrents et al., PMID:10080182 AND Borsani et al., PMID:10080183). At least 9 variants (e.g. missense, nonsense, frameshift, large deletion, etc) have been reported in humans, with many more being provided in the literature. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 8 probands in 3 publications (PMIDs: 10080182, 10080183, 15776247). Variants in this gene segregated with disease in 2 additional family members. Significantly more evidence and probands are available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function, with the mutated proteins not able to fulfill their function of amino acid transport through the plasma membrane causing CAA homeostasis alterations and resulting in the displayed symptoms like vomiting, protein avoidance, and growth delay. This gene-disease association is supported by animal models, expression studies, in vitro functional assays, and biochemical function evidence. The null mouse model markedly recapitulates the phenotype of the human probands, as does the cultured patient macrophage cells demonstrate the altered CAA transport and its resulting effects. The protein's primary expression in the kidney is also notable because of the disease mechanism of reduced CAA uptake in the kidney. In summary, SLC7A7 is definitively associated with Autosomal Recessive Lysinuric Protein Intolerance. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Working Group on 11/08/19 (SOP Version 007).
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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