Submissions for variant NM_000275.3(OCA2):c.2425T>A (p.Phe809Ile)

gnomAD frequency: 0.00009  dbSNP: rs765779905

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176361	SCV000228002	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000504183	SCV000596138	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2016-03-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000176361	SCV001793690	likely pathogenic	not provided	2022-12-21	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: 29345414)
Genome-Nilou Lab	RCV000504183	SCV002039330	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000176361	SCV002135553	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 809 of the OCA2 protein (p.Phe809Ile). This variant is present in population databases (rs765779905, gnomAD 0.05%). This missense change has been observed in individual(s) with ocular albinism (PMID: 29345414; Invitae). 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: 195725). 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.
Revvity Omics, Revvity	RCV000176361	SCV003814238	uncertain significance	not provided	2019-08-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416081	SCV004113321	likely pathogenic	OCA2-related condition	2022-08-24	criteria provided, single submitter	clinical testing	The OCA2 c.2425T>A variant is predicted to result in the amino acid substitution p.Phe809Ile. This variant has been reported along with a second OCA2 variant in at least two unrelated individuals with oculocutaneous albinism (Supplemental Table 3 in Lasseaux et al. 2018. PubMed ID: 29345414). Additionally, we have observed this variant here at PreventionGenetics in several individuals with oculocutaneous albinism who also harbored a second pathogenic variant in OCA2. This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-28090112-A-T). This variant has conflicting interpretations in the ClinVar database including uncertain, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/195725). Given the evidence, we interpret c.2425T>A (p.Phe809Ile) as likely pathogenic.
Baylor Genetics	RCV003468859	SCV004209034	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-05-17	criteria provided, single submitter	clinical testing