ClinVar Genomic variation as it relates to human health

Reported previously in association with oculocutaneous albinism in published literature, either as a single heterozygous variant or phase unknown with a second variant (PMID: 26474496, 28451379, 32830442); 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: 10671067, 32830442, 23824587, 28451379, 26474496, 37882226, 37650133, 38219857)

PM3_Strong, PP3, PM1

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the OCA2 protein (p.Ala368Val). This variant is present in population databases (rs61745150, gnomAD 0.3%). This missense change has been observed in individual(s) with ocular albinism (PMID: 28451379; 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: 193574). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OCA2 protein function. For these reasons, this variant has been classified as Pathogenic.

This OCA2 variant (rs61745150) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomAD: 70/24946 alleles; 0.28%, no homozygotes). This patient's ethnicity is reported to be African American. This variant has been reported to ClinVar. It has been identified on the opposite chromosome from a pathogenic variant in unrelated individuals with OCA, type II. Two bioinformatic tools queried predict that this substitution (p.Ala368Val) would be damaging, and the alanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 10 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1103C>T to be likely pathogenic.

The c.1103C>T (p.A368V) alteration is located in exon 10 (coding exon 9) of the OCA2 gene. This alteration results from a C to T substitution at nucleotide position 1103, causing the alanine (A) at amino acid position 368 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.026% (73/282508) total alleles studied. The highest observed frequency was 0.281% (70/24946) of African alleles. This variant has been identified in the homozygous state and/or in conjunction with other OCA2 variants in individuals with features consistent with OCA2-related oculocutaneous albinism; in at least one instance, the variants were identified in trans (Ambry internal data; Gao, 2017; Michaud, 2023). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Variant summary: OCA2 c.1103C>T (p.Ala368Val) 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 0.00022 in 251112 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00022 vs 0.0043), allowing no conclusion about variant significance. c.1103C>T has been observed in multiple compound heterozygous and homozygous individuals affected with Oculocutaneous Albinism (example: Jackson_2020, Gao_2017, Wolfson_2016, Oetting_1998, Michaud_2024). These data indicate that the variant is associated with disease. 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: 32830442, 28451379, 37650133, 10671067, 26474496). ClinVar contains an entry for this variant (Variation ID: 193574). Based on the evidence outlined above, the variant was classified as pathogenic.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.