Submissions for variant NM_000275.3(OCA2):c.1025A>G (p.Tyr342Cys)

gnomAD frequency: 0.00025  dbSNP: rs142931246

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001574644	SCV001801500	likely pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	Identified in two families with cutaneous malignant melanoma including one individual who harbored a second OCA2 missense variant of unknown phase (PMID: 29036293); 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: 31589614, 28224992, 23824587, 28667292, 34426522, 27734839, 34897530, 19060277, 29036293, 29345414)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001574644	SCV002195907	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 342 of the OCA2 protein (p.Tyr342Cys). This variant is present in population databases (rs142931246, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of ocular albinism (PMID: 19060277, 27734839, 29345414). ClinVar contains an entry for this variant (Variation ID: 373910). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155175	SCV003844840	pathogenic	Oculocutaneous albinism	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1025A>G (p.Tyr342Cys) 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. The variant allele was found at a frequency of 0.00025 in 250798 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00025 vs 0.0043), allowing no conclusion about variant significance. c.1025A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Oculocutaneous Albinism (e.g. Mauri_2017, Norman_2017, Lasseaux_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470362	SCV004208975	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-24	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415383	SCV000492537	likely pathogenic	Albinism	2016-04-06	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001574644	SCV001959106	uncertain significance	not provided		flagged submission	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001574644	SCV001967473	uncertain significance	not provided		flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001574644	SCV001978547	uncertain significance	not provided		flagged submission	clinical testing
Genome-Nilou Lab	RCV001116802	SCV002040070	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401404	SCV004104030	likely pathogenic	OCA2-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The OCA2 c.1025A>G variant is predicted to result in the amino acid substitution p.Tyr342Cys. This variant has been reported in the compound heterozygous state, along with a pathogenic variant, in one patient with ocular albinism (Norman et al. 2017. PubMed ID: 28667292, proband 16 in Table 2). This variant has also been reported in two patients, one with retinal dystrophy and another with ocular albinism (Haer-Wigman. 2017. PubMed ID: 28224992, Patient ID: 4795B; Grønskov. 2009. PubMed ID: 19060277; TABLE 3B, Patient ID: 2). A second causative variant was not identified in these patients. At PreventionGenetics, this variant along with another pathogenic or likely pathogenic variant was found in at least three patients with oculocutaneous albinism (OCA). Taken together, we consider the c.1025A>G (p.Tyr342Cys) variant as likely pathogenic.