Submission Details

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. Phenotypes associated include iris hypopigmentation, reduction in hair, skin, and eye pigment, abnormality of the optic nerve, nystagmus, photophobia, strabismus, and visual impairment (PMID:17980020). OCA is further broken down by type based on phenotypic differences. Oculocutaneous albinism type 2 is less severe than type 1 with skin and hair pigmentation ranging from minimal to near normal. Variants in OCA2 were first reported in relation to OCA2 in 1993 by Rinchik et al (PMID:8421497). Variants in OCA2 account for approximately 30% of worldwide cases of oculocutaneous albinism type 2 (at least 154 unique variants have been reported) (PMID:32963319). Evidence from 26 probands in 7 publications have been included in this curation, representing 31 unique variants (missense, nonsense, frameshift, and splice site) (PMIDs:115712365, 1906277, 33612058, 19865097, 28726809, 29345414, 33808351). Of note, the most common OCA2 variant among African individuals with oculocutaneous albinism, previously referred to in the literature as Brown oculocutaneous albinism [MIM:203200], is a 2.7 kb deletion; this variant is thought to account for ~20% of African cases (PMID:21085994). Please note that because the pigmentary phenotype due to pathogenic variants in OCA2 and other OCA genes can appear different in individuals of African descent. Per ClinGen Lumping and Splitting guidelines, the General Gene Curation Expert Panel has not identified a difference in phenotypes associated with both disease entities or types of variants associated with either presentation. Therefore, the GCEP has decided to lump this entity into this curation. The gene-disease relationship between oculocutaneous albinism type 2 and OCA2 is supported by evidence for protein interaction in melanocytes between the P protein encoded by OCA2 and both tyrosinase, and tyrosinase related protein 1 (encoded by two other genes, TYR and TYRP1, known to also be associated with oculocutaneous albinism) (PMID:19060277). Additionally, there are multiple animal models available to support this gene-disease relationship, including mice (PMIDs:1495987, 1509264, 8421497), German Spitz dogs (PMID:28973042), and Rhesus macaques (PMID:32259106). In summary there is definitive evidence supporting a gene-disease relationship between variants in OCA2 and oculocutaneous albinism type 2. This classification has been approved by the ClinGen General Gene Curation Expert Panel on 8/25/2021.