Submission Details

The relationship between TYR and oculocutaneous albinism type 1 (OCA1) was evaluated using the ClinGen Clinical Validity Framework as of August 14, 2020. Oculocutaneous albinism (OCA) is an autosomal recessive disorder of melanin synthesis associated with a reduction of melanin pigment in the skin, hair, and eyes. Reduction of melanin in the eyes is associated with foveal hypoplasia and decreased visual acuity, misrouting of the optic nerve fibres from the retina to the visual cortex, nystagmus, strabismus and iris translucency (Oetting et al, 2003, PMID 12753405; Lewis, 2013, PMID 20301345). Notably, several genes have been implicated in OCA, and syndromic and non-syndromic forms of albinism have been described (Federico and Krishnamurthy, 2020, PMID 30085560). TYR, which has been implicated in OCA1, encodes tyrosinase, a copper-containing monooxygenase with a key role melanin synthesis. Melanin is made, stored and transported in pigment granules (melanosomes) in mammalian skin melanocytes, choroidal melanocytes and retinal pigment epithelial (RPE) cells in the eye (Wasmeier et al, 2008, PMID 19056669). Two types of OCA1 are described in the literature. OCA1A (historically known as “tyrosinase-negative OCA”), is the most severe form of the disorder. Tyrosinase activity is completely absent, and melanin pigment cannot be detected in the skin, hair or eyes of individuals with OCA1. There is low tyrosinase activity in individuals with OCA1B but some residual activity is present allowing some melanin to be produced, albeit at a reduced amount. Biallelic variants in TYR were first reported in 1989 (Tomita et al, PMID 2511845). Since then, more than 300 variants have been reported in TYR (PMID 30868138). Data from 9 probands who are homozygous or compound heterozygous for TYR variants were curated, including 12 unique variants (missense, nonsense, frameshift, splice site) (Tomita et al, 1989, PMID 2511845; Monfermé et al, 2019, PMID 30472657; Shakil et al, 2019, PMID 30996339; Lin et al, 2019, PMID 31199599; Schidlowski et al, 2020, PMID 32411182). This gene-disease relationship is supported by the biochemical role of TYR in the synthesis of melanin, which is consistent with the lack of pigmentation observed in individuals with OCA1 (Raper, 1926, PMID 16743714; Lai etal, 2018, PMID 29052256), functional alteration studies (Spritz et al, 1997, PMID 9242509; Totofuku et al, 2001, PMID 11284711), numerous natural and laboratory animal models including a spontaneous variant in mice (Le Fur et al, 1996, PMID 8921397), CRISPR-generated albino mice (Mizuno et al, 2014, OMID 24879364), and rescue of the phenotype by expression of tyrosinase in transgenic albino mice and medaka fish (Jeffery et al, 1994, PMID 7813769; Fu et al, 2000, PMID 10675031). In summary, TYR is definitively associated with OCA1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.