Submissions for variant NM_000275.3(OCA2):c.1363A>G (p.Arg455Gly)

gnomAD frequency: 0.00010  dbSNP: rs200764804

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778422	SCV000914661	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2018-12-03	criteria provided, single submitter	clinical testing	The OCA2 c.1363A>G (p.Arg455Gly) has been reported in one study and was found in three individuals diagnosed with oculocutaneous albinism from the Chinese Han population (Wei et al. 2010). An affected male was compound heterozygous for p.Arg455Gly with a second nonsense variant. The variant was found in a heterozygous state in the two further affected individuals. The p.Arg455Gly variant was absent from 100 Han Chinese control subjects and is reported at a frequency of 0.016 in the Chinese Dai population of the 1000 Genomes Project. Based on the evidence the p.Arg455Gly variant is classified as a variant of unknown significance but suspicious for pathogenicity for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001339980	SCV001533765	pathogenic	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 455 of the OCA2 protein (p.Arg455Gly). This variant is present in population databases (rs200764804, gnomAD 0.3%). This missense change has been observed in individual(s) with ocular albinism (PMID: 19865097, 31196117, 33974259). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 631723). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000778422	SCV002040170	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778422	SCV002767979	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism (MIM#203200) and oculocutaneous albinism, type II (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 24518832, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 69 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 169 heterozygotes, 1 homozygote). (I) 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 citrate transporter domain (PDB). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported twice in ClinVar as a variant of unknown significance, however it has also been observed in at least 4 patients with oculocutaneous albinism. In particular, this variant has been observed in trans with p.(Val443Ile) in 1 individual clinically diagnosed with oculocutaneous albinism (PMID: 31196117, 19865097). (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) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002487598	SCV002781855	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155310	SCV003844683	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1363A>G (p.Arg455Gly) results in a non-conservative amino acid change located in the citrate transporter-like domain (IPR004680) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site and creates a new 3' acceptor site, and one tool predicts that the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00026 in 249888 control chromosomes, predominantly at a frequency of 0.0033 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00026 vs 0.0043), allowing no conclusion about variant significance. c.1363A>G has been reported in the literature in the heterozygous and compound heterozygous state in individuals of East Asian/Chinese ancestry affected with Oculocutaneous Albinism, including one case where it was confirmed to be in trans with a pathogenic variant (e.g. Wei_2010, Yang_2019, Ma_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=4) or likely pathogenic (n=1) Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003461049	SCV004208969	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-29	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002487598	SCV005417218	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES		criteria provided, single submitter	clinical testing	BS1+PM3_VeryStrong+PP4+PP3