The relationship between SLC52A3 and autosomal recessive Brown-Vialetto-Van Laere syndrome (BVVL) was evaluated using the ClinGen Clinical Validity Framework as of 9/12/2018. Variants in SLC52A3 were first reported in humans with this disease as early as 2010 (Green et al., PMID 20206331). SLC52A3 is associated with the childhood onset neurodegenerative syndrome Brown–Vialetto–Van Laere (BVVL) which is characterized by sensorineural hearing loss and ponto-bulbar palsy (PMID: 26976849, 30420458). Whilst these are the most common clinical features, BVVL can also present without either symptom (PMID: 26973221). The standard treatment for BVVL is riboflavin supplementation which is associated with favourable clinical outcomes (PMID: 26973221). At least 25 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and mouse models, a drosophila model, biochemical function studies implicating the gene's role in riboflavin uptake, and functional alteration studies showing that alteration to the gene impairs riboflavin uptake which appears to be the mechanism for disease. Variants in this gene have been reported in at least 22 probands in 5 publications (PMIDs: 29053833, 25462087, 21110228, 20206331, 22824638). Variants in this gene segregated with disease in 2 additional family members. In summary, SLC52A3 is definitively associated with autosomal recessive Brown-Vialetto-Van Laere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 9/18/2018. It was reevaluated on 6/21/2023 in collaboration with the Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP. As a result of this reevaluation, the classification did not change. However, scoring was adjusted to the current Gene Clinical Validity SOP Version 9. It is also worth highlighting that in the mouse and drosophila models (PMID: 27272163, 29053833) riboflavin supplementation was able to restore normal function and replicates the rescue of the phenotypes observed in humans with Brown-Vialetto-Van Laere syndrome (PMID: 30420458).
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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