Submissions for variant NM_000275.3(OCA2):c.1336A>G (p.Met446Val)

gnomAD frequency: 0.00044  dbSNP: rs140566426

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001119693	SCV001278123	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.
Invitae	RCV002069944	SCV002415838	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235472	SCV003934422	uncertain significance	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1336A>G (p.Met446Val) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 281578 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.0002 vs 0.0043), allowing no conclusion about variant significance. c.1336A>G has been reported in the literature in at least one compound heterozygous individual affected with Oculocutaneous Albinism (Hutton_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18326704, 9259203). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001119693	SCV004100712	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2023-10-16	criteria provided, single submitter	clinical testing	Criteria applied: PS4_SUP,PM2_SUP