ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.1327G>A (p.Val443Ile) (rs121918166)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623104 SCV000742020 pathogenic Inborn genetic diseases 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477815 SCV000536763 likely pathogenic Tyrosinase-positive oculocutaneous albinism; Skin/hair/eye pigmentation, variation in, 1 2014-11-13 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000310636 SCV000225767 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000477815 SCV000611223 pathogenic Tyrosinase-positive oculocutaneous albinism; Skin/hair/eye pigmentation, variation in, 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000310636 SCV000329644 pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The V443I pathogenic variant in the OCA2 gene has been reported previously multiple times in both the homozygous state and in trans with another OCA2 variant in association with oculocutaneous albinism (Lee et al., 1994; Hutton and Spritz, 2008). The V443I variant is observed in 639/125,694 (0.05%) alleles from individuals of non-Finnish European background, including multiple unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). The V443I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, functional studies demonstrate that the V443I variant disrupts ion conductance, which is required for melanin production (Bellono et al., 2014). We interpret V443I as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000001006 SCV000248365 pathogenic Tyrosinase-positive oculocutaneous albinism 2015-04-17 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000001006 SCV000584106 pathogenic Tyrosinase-positive oculocutaneous albinism 2014-09-11 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000001006 SCV000390147 pathogenic Tyrosinase-positive oculocutaneous albinism 2019-04-05 criteria provided, single submitter clinical testing The OCA2 c.1327G>A (p.Val443Ile) missense variant has been described as the most common pathogenic variant for oculocutaneous albinism type 2 (OCA) in northern European populations (Lewis et al. 2012). Across a selection of the literature, the p.Val443Ile variant has been reported in at least six studies in which it is found in a total of 15 patients with OCA, including in two in a homozygous state, in ten in a compound heterozygous state, and in three in a heterozygous state (Lee et al. 1994; Oetting et al. 2005; Hutton et al. 2008; Gargiulo et al. 2011; Zhang et al. 2013; Wei et al. 2015). One homozygote and one compound heterozygote also carried variants in other OCA-related genes. In at least three families, unaffected parents were found to be heterozygous for the p.Val443Ile variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00628 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the p.Val443Ile variant protein localized similarly to wild type but showed reduced activity of 85% and reduced pH regulation compared to wild-type (Bellono et al. 2014). Based on the collective evidence, the p.Val443Ile variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000001006 SCV000966900 pathogenic Tyrosinase-positive oculocutaneous albinism 2018-02-06 criteria provided, single submitter clinical testing The p.Val443Ile variant in OCA2 has been reported in the homozygous or compound heterozygous state in >10 individuals with oculocutaneous albinism (OCA) type 2, including 1 de novo occurrence (Oetting 2005, Hutton 2008, Gargiulo 2011, Zhang 2013, Wolfson 2016, Andersen 2016, Gao 2017). This variant is reported to be th e most common pathogenic OCA2 variant in northern European populations (Hutton 2 008, Lewis 2012) and has been identified in 0.5% (639/125694) of European chromo somes, including 4 homozygous individuals, by the Genome Aggregation Database (g nomAD,; dbSNP rs121918166). This frequency is c onsistent with the carrier frequency for OCA type 2. In vitro studies demonstrat ed that the p.Val443Ile variant results in a partial loss of protein function (S viderskaya 1997, Bellono 2014). In summary, this variant meets criteria to be cl assified as pathogenic for OCA type 2 in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_Very Strong; PM6; PS3_Supporting; PP4.
OMIM RCV000001006 SCV000021156 pathogenic Tyrosinase-positive oculocutaneous albinism 1994-02-24 no assertion criteria provided literature only

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