The relationship between SLC36A2 and iminoglycinuria was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2024. Iminoglycinuria is defined as excess urinary excretion of proline, hydroxyproline, and glycine, and is thought to be benign. Variants in SLC36A2 were first reported in individuals with iminoglycinuria in 2008 (Broer et al, PMID 19033659). The authors report one family in which a child who is homozygous for a canonical splice site variant has iminoglycinuria. Two siblings and both parents were heterozygous for the variant and have hyperglycinuria. In a further four families, individuals with iminoglycinuria were reported to be homozygous for a missense variant (p.Gly87Val, resulting in 50% normal transport activity) in SLC36A2 and heterozygous for a missense variant in another gene, SLC6A20 (families 1-3), or homozygous for an intronic variant affecting branch point selection in SLCA19 (family 4). One individual who is homozygous for p.Gly87Val in SLC36A2 without additional changes in SLC6A20 or SLC6A19 was reported to have hyperglycinuria but normal urinary proline and hydroxyproline levels. Thus it appears that for less severe variants in SLC36A2, the contribution of variants in other genes involved in amino acid transport may be required for iminoglycinuria. Another individual has been reported who is homozygous for a nonsense variant in SLC36A2 (PMID 26141664). This individual has multiple congenital anomalies, most likely not caused by the SLC36A2 variant. No details are available regarding the urine proline, hydroxyproline, and glycine levels for this patient. This gene-disease relationship is supported by the function of SLC36A2 (also known as PAT2) as a high affinity transporter of proline and glycine (Boll et al, 2002, PMID 11959859; Boll et al, 2003, PMID 12809675), and expression of SLC36A2 in the kidney (https://gtexportal.org/home/gene/SLC36A2, PMID 25954001). In summary, there is limited evidence to support the relationship between SLC36A2 and iminoglycinuria. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This classification was originally approved by the Aminoacidopathy Gene Curation Expert Panel on March 13, 2020. This gene-disease relationship was re-evaluated on March 7, 2024. As a result of this re-evaluation, the classification did not change.
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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