Submissions for variant NM_000275.3(OCA2):c.1255C>T (p.Arg419Trp)

gnomAD frequency: 0.00054  dbSNP: rs143218168

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174460	SCV000225766	uncertain significance	not provided	2014-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121675	SCV001280316	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000174460	SCV001489513	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 419 of the OCA2 protein (p.Arg419Trp). This variant is present in population databases (rs143218168, gnomAD 0.2%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 9259203, 21458243, 29345414, 31077556). 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: 194160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx	RCV000174460	SCV001821016	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	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: 31229681, 9259203, 30025130, 30414346, 34426522, 31077556, 32552135, 34707637, 33124154, 34838614, 33808351, 37194472, 35488210)
Genome-Nilou Lab	RCV001121675	SCV002039970	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001121675	SCV002768005	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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous 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 albininism are known to have variable expressivity (PMID: 24518832). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (78 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12158 heterozygotes, 400 homozygotes). (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 permease P domain (NCBI). (I) 0710 - Another missense variant has inconclusive previous evidence for pathogenicity. This alternative change at the same position (p.Arg419Gln) has been reported multiple times as benign and as a polymorphism, but has a weaker Grantham change (LOVD, ClinVar, PMID: 9259203). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as a VUS (ClinVar), but more recently described as pathogenic and observed in many compound heterozygous patients with oculocutaneous albinism (PMID: 9259203, PMID: 33124154; PMID: 23504663; PMID: 31229681; PMID: 29095814; PMID: 31077556). One patient also had occult macular dystrophy, but this is due to an additional variant in the RPL1L1 gene (PMID: 30025130). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003462278	SCV004208972	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742309	SCV005362695	likely pathogenic	OCA2-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The OCA2 c.1255C>T variant is predicted to result in the amino acid substitution p.Arg419Trp. This variant has been reported in individuals with autosomal recessive oculocutaneous albanism (OCA) (Spritz et al. 1997. PubMed ID: 9259203; Zobor et al. 2018. PubMed ID: 30025130; Zhong et al. 2019. PubMed ID: 31077556). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.