ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.1320G>C (p.Leu440Phe) (rs1800408)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000243597 SCV000303421 benign not specified 2016-02-05 criteria provided, single submitter clinical testing
GeneDx RCV000766763 SCV000589909 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing The L440F variant in the OCA2 gene has been reported previously in both the heterozygous and homozygous state in several individuals with oculocutaneous albinism, however, many of these individuals also harbored additional variants in the OCA2 gene or in other genes that may also have contributed to their clinical phenotype (Lee et al., 1995; Spritz et al., 1997; Hutton et al., 2008a; Hutton et al., 2008b). Additional evidence to suggest pathogenicity or benign classification of the L440F variant was not provided in these studies. The L440F variant is observed in 35/65824 (0.053%) alleles from individuals of European (Non-Finnish) background, with no homozygous individuals reported, in the ExAC data set (Lek et al., 2016). The L440F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L440F as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000243597 SCV000596145 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000243597 SCV000706941 likely benign not specified 2017-03-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001119694 SCV001278124 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000766763 SCV001581546 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 440 of the OCA2 protein (p.Leu440Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs1800408, ExAC 0.05%). This variant has been observed in individual(s) with oculocutaneous albinism (PMID: 18463683, 18326704, 29345414, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 255719). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

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