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

gnomAD frequency: 0.00024  dbSNP: rs1800408

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766763	SCV000589909	likely pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Identified in both the heterozygous and homozygous state in several individuals with oculocutaneous albinism in published literature, although some of these individuals also harbored additional variants (including G27R) in the OCA2 gene or in other genes that may also have contributed to their clinical phenotype; additional evidence to suggest pathogenicity or benign classification of the L440F variant was not provided in these studies (PMID: 7601462, 9259203, 18326704, 18463683); Observed with p.(G27R) on the same allele (in cis) in multiple unrelated individuals referred for genetic testing at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in both the heterozygous and homozygous state in several individuals with oculocutaneous albinism in published literature, although some of these individuals also harbored additional variants (including G27R) in the OCA2 gene or in other genes that may also have contributed to their clinical phenotype; additional evidence to suggest pathogenicity or benign classification of the L440F variant was not provided in these studies (PMID: 7601462, 9259203, 18326704, 18463683); Identified in both the heterozygous and homozygous state in several individuals with oculocutaneous albinism in published literature, although some of these individuals also harbored additional variants (including G27R) in the OCA2 gene or in other genes that may also have contributed to their clinical phenotype; additional evidence to suggest pathogenicity or benign classification of the L440F variant was not provided in these studies (PMID: 7601462, 9259203, 18326704, 18463683); This variant is associated with the following publications: (PMID: 12163334, 15889046, 17236130, 18463683, 9259203, 18326704, 23824587, 29345414, 18839200, 32830442, 23504663, 7601462, 38219857, 39201349)
Genetic Services Laboratory, University of Chicago	RCV000243597	SCV000596145	uncertain significance	not specified	2016-12-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766763	SCV001581546	pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 440 of the OCA2 protein (p.Leu440Phe). This variant is present in population databases (rs1800408, gnomAD 0.8%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 18326704, 18463683, 29345414; internal data). 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: 255719). 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%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001119694	SCV002039881	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519877	SCV003701417	uncertain significance	Inborn genetic diseases	2021-08-19	criteria provided, single submitter	clinical testing	The c.1320G>C (p.L440F) alteration is located in exon 13 (coding exon 12) of the OCA2 gene. This alteration results from a G to C substitution at nucleotide position 1320, causing the leucine (L) at amino acid position 440 to be replaced by a phenylalanine (F). Based on data from gnomAD, the C allele has an overall frequency of 0.04% (109/281,394) total alleles studied. The highest observed frequency was 0.84% (87/10,322) of Ashkenazi Jewish alleles. This alteration was reported in two patients with oculocutaneous albinism type 2; one patient was homozygous for this alteration and the other was compound heterozygous with another missense alteration, c.1327G>A, (p.V443I) (Jackson, 2020). This variant has also been reported in additional patients with either limited clinical info (Simeonov, 2013; Lasseaux, 2018) or with multiple variants in this and other OCA genes (Hutton, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003469193	SCV004208973	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766763	SCV004238318	likely pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003594	SCV005630578	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055795	SCV005725620	pathogenic	Oculocutaneous albinism	2024-11-27	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1320G>C (p.Leu440Phe) results in a non-conservative amino acid change located in the Citrate transporter-like domain 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 0.00042 in 250002 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00042 vs 0.0043), allowing no conclusion about variant significance. c.1320G>C has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (examples: Lasseaux_2018, Lin_2024, Internal data). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29345414, 38219857, No_PMID). ClinVar contains an entry for this variant (Variation ID: 255719). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003389640	SCV000303421	uncertain significance	OCA2-related disorder	2023-10-20	no assertion criteria provided	clinical testing	The OCA2 c.1320G>C variant is predicted to result in the amino acid substitution p.Leu440Phe. This variant has been reported in the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (Table S3 in Lasseaux et al. 2018. PubMed ID: 29345414; Jackson et al. 2020. PubMed ID: 32830442). This variant has also been reported as a "third" variant in an individual who was homozygous for the OCA2 variant c.79G>A (p.Gly27Arg) (Hutton et al. 2008. PubMed ID: 18326704). This variant is reported in 0.84% of alleles in individuals of Ashkenazi Jewish descent and with a global allele frequency of 0.039% in gnomAD (http://gnomad.broadinstitute.org/variant/15-28230254-C-G), which is higher than expected for a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Eurofins Ntd Llc (ga)	RCV000243597	SCV000706941	likely benign	not specified	2017-03-27	flagged submission	clinical testing