Submissions for variant NM_000275.3(OCA2):c.2330G>A (p.Cys777Tyr)

gnomAD frequency: 0.00001  dbSNP: rs776814755

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493655	SCV000582329	likely pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Observed with a second OCA2 variant in an individual with clinical oculocutaneous albinism, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ma L et al., 2021); Identified in two families with cutaneous malignant melanoma, including one individual who harbored a second OCA2 missense variant, but additional clinical information was not provided (Goldstein et al., 2017); Identified as a single heterozygous variant in a proband with features of oculocutaneous albinism (Marti et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32966289, 29036293, 34707637, 28976636)
Fulgent Genetics, Fulgent Genetics	RCV000762937	SCV000893360	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000493655	SCV002314095	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 777 of the OCA2 protein (p.Cys777Tyr). This variant is present in population databases (rs776814755, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of oculocutaneous albinism (PMID: 28976636; internal data). ClinVar contains an entry for this variant (Variation ID: 429697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt OCA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470881	SCV002767262	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism and oculocutaneous, type II albinism (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. A single variant has been reported in two families with dominant oculocutaneous albinism (PMID: 32741191). (I) 0115 - Variants in this gene causing oculocutaneous albinism are known to have variable expressivity (PMID: 24518832). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (8 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane helix within the permease P domain (NCBI). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change p.(Cys777Arg) has been reported in a heterozygous patient with albinism (PMID: 20861488). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as likely pathogenic (ClinVar), and has been observed in a heterozygous patient with albinism (PMID: 28976636). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV002470881	SCV003804559	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470613	SCV004209015	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-08-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742450	SCV005360256	uncertain significance	OCA2-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The OCA2 c.2330G>A variant is predicted to result in the amino acid substitution p.Cys777Tyr. This variant has been reported in an individual with oculocutaneous albinism, but a second variant in the OCA2 gene was not detected (Marti et al. 2017. PubMed ID: 28976636). This variant has also been reported along with a variant of uncertain significance in OCA2 in an individual with oculocutaneous albinism (Ma et al. 2021. PubMed ID: 34707637). Additionally this variant has been reported in the heterozygous state in individuals who developed cutaneous malignant melanoma (Goldstein et al. 2017. PubMed ID: 29036293). This variant is documented in 0.011% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.