The relationship between SLC19A3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 14, 2019. 31 articles were reviewed. SLC19A3 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2013 (Gerards et al., PMID: 23423671). At least 25 unique variants have been reported in humans. 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 6 probands with Leigh syndrome spectrum in 6 publications (PMIDs 23482991, 24878502, 23589815, 24166474, 26975589, 27896110) and variants in this gene segregated with disease in three additional family members (PMID: 23423671). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function and animal models. The mechanism for disease is thiamine transporter deficiency. Of note, this gene has also been implicated in biotin-thiamine-responsive basal ganglia disease. This phenotype will be assessed separately. In summary, there is definitive evidence to support the relationship between SLC19A3 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 14, 2019 (SOP Version 6).
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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