ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.1178G>T (p.Gly393Val)

gnomAD frequency: 0.00001  dbSNP: rs749661379
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001884356 SCV002156512 pathogenic not provided 2024-06-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 393 of the OCA2 protein (p.Gly393Val). This variant is present in population databases (rs749661379, gnomAD 0.007%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 34707637; Invitae). 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: 1388008). 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.
GeneDx RCV001884356 SCV004014221 likely pathogenic not provided 2023-07-13 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34707637, 34838614)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017879 SCV004847491 likely pathogenic Tyrosinase-positive oculocutaneous albinism 2024-04-16 criteria provided, single submitter clinical testing The p.Gly393Val variant in OCA2 has been reported in the homozygous state in 1 individual and in the compound heterozygous state with another potentially disease-causing variant in 3 individuals with oculocutaneous albinism, and the variants were confirmed in trans in at least 1 individual (Ma 2021 PMID: 34707637, Wei 2022 PMID: 34838614, Invitae pers. comm.). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 1388008) and has been identified in 0.009% (7/74926) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0), consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive oculocutaneous albinism. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526875 SCV005040229 uncertain significance not specified 2024-03-15 criteria provided, single submitter clinical testing Variant summary: OCA2 c.1178G>T (p.Gly393Val) 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 4e-06 in 251300 control chromosomes (gnomAD). c.1178G>T has been reported in the literature in individuals affected with Tyrosinase-Positive Oculocutaneous Albinism (Ma_2021, Wei_2022). These data indicate that the variant may be 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: 34707637, 34838614). ClinVar contains an entry for this variant (Variation ID: 1388008). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005006159 SCV005630585 likely pathogenic Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES 2024-03-19 criteria provided, single submitter clinical testing

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