Submissions for variant NM_000275.3(OCA2):c.1465A>G (p.Asn489Asp)

gnomAD frequency: 0.00043  dbSNP: rs121918170

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000413429	SCV000226011	pathogenic	not provided	2017-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000413429	SCV000490675	pathogenic	not provided	2024-09-12	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: 13680365, 30665703, 31233279, 9259203, 19060277, 23824587, 23345203, 25513726, 20801516, 12876664, 18326704, 18463683, 24118800, 21541274, 29345414, 28667292, 30414346, 31206972, 31980526, 31589614, 34361043, 38219857, 34758253, 34662886)
Genetic Services Laboratory, University of Chicago	RCV000001012	SCV000596144	pathogenic	Tyrosinase-positive oculocutaneous albinism	2016-10-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762940	SCV000893363	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001012	SCV000914660	pathogenic	Tyrosinase-positive oculocutaneous albinism	2018-10-19	criteria provided, single submitter	clinical testing	The TCN2 c.497_498delTC (p.Leu166ProfsTer7) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu166ProfsTer7 variant has been reported in two studies and is found in a total of four unrelated probands with transcobalamin II deficiency including three in a homozygous state and one in a compound heterozygous state (Schiff et al. 2010; Trakadis et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Leu166ProfsTer7 variant is classified as pathogenic for transcobalamin II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000413429	SCV001250100	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	OCA2: PM3:Very Strong, PM2, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413429	SCV001584382	pathogenic	not provided	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 489 of the OCA2 protein (p.Asn489Asp). This variant is present in population databases (rs121918170, gnomAD 0.07%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 12876664, 18463683, 29345414). 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: 961). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on OCA2 function (PMID: 25513726). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000413429	SCV002020182	likely pathogenic	not provided	2021-07-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000001012	SCV002040586	pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466774	SCV004208966	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492280	SCV004240913	pathogenic	Oculocutaneous albinism	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1465A>G (p.Asn489Asp) results in a conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251496 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00035 vs 0.0043), allowing no conclusion about variant significance. c.1465A>G has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (example: Lasseaux_2018). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29345414). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000001012	SCV000021162	pathogenic	Tyrosinase-positive oculocutaneous albinism	2003-09-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000413429	SCV001741823	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000001012	SCV001760340	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000413429	SCV001921089	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413429	SCV001958831	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413429	SCV001973382	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000001012	SCV004099433	pathogenic	Tyrosinase-positive oculocutaneous albinism	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421891	SCV004118645	pathogenic	OCA2-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The OCA2 c.1465A>G variant is predicted to result in the amino acid substitution p.Asn489Asp. This variant has been reported to be causative for autosomal recessive oculocutaneous albinism (Spritz et al. 1997. PubMed ID: 9259203; King et al. 2003. PubMed ID: 13680365; King et al. 2003. PubMed ID: 12876664; Hutton and Spritz. 2008. PubMed ID: 18326704). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported to be one of three recurrent pathogenic variants in the OCA2 gene and accounts for one of the alleles in ~7% of OCAII cases (Hutton and Spritz. 2008. PubMed ID: 18463683). Given the evidence, we interpret this variant as pathogenic.