ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.1453G>A (p.Gly485Arg)

dbSNP: rs747214535
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000270433 SCV000390141 uncertain significance Tyrosinase-positive oculocutaneous albinism 2017-04-27 criteria provided, single submitter clinical testing The OCA2 c.1453G>A (p.Gly485Arg) missense variant has been reported in one study in which it is found in a homozygous state in two unrelated patients with oculocutaneous albinism. The variant was present in a heterozygous state in at least four unaffected family members (Renugadevi et al. 2010). The variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. The Gly485 residue is conserved. Based on the evidence, the Gly485Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago RCV001820933 SCV002069095 likely pathogenic not provided 2018-02-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001820933 SCV003443451 uncertain significance not provided 2022-10-16 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly485 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (PMID: 18821858, 29345414), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 315466). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 20806075). This variant is present in population databases (rs747214535, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 485 of the OCA2 protein (p.Gly485Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689714 SCV005184365 likely pathogenic Oculocutaneous albinism 2024-05-01 criteria provided, single submitter clinical testing Variant summary: OCA2 c.1453G>A (p.Gly485Arg) 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 251496 control chromosomes. c.1453G>A has been reported in the literature in homozygous state in individuals affected with Oculocutaneous Albinism (Renugadevi_2009, Renugadevi_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense change affecting the same amino acid (G485V) is reported in affected individuals (PMID: 19060277, 29345414; see HGDM) and is classified as likely pathogenic in ClinVar, indicating that this residue might be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19309806, 20806075). ClinVar contains an entry for this variant (Variation ID: 315466). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005010275 SCV005630572 likely pathogenic Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES 2024-05-28 criteria provided, single submitter clinical testing

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