ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.79G>A (p.Gly27Arg) (rs61738394)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727245 SCV000589529 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing The G27R variant in the OCA2 gene has been reported previously in the homozygous and compound heterozygous state in multiple individuals with OCA type 2 (Spritz et al., 1997; Oetting et al., 2005; Hutton et al., 2008a; Hutton et al., 2008b; Rosenmann et al., 2009). Many of these affected individuals also carried heterozygous and/or homozygous variants in other genes associated with oculocutaneous albinism that were classified as benign, however, supporting evidence for those classifications was not provided (Hutton et al., 2008a; Hutton et al., 2008b). The G27R variant is observed in 111/8044 (1.38%) alleles from individuals of African background, with 2 homozygous individuals reported, in the ExAC data set (Lek et al., 2016). The G27R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret G27R as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV001172458 SCV000596151 uncertain significance not specified 2017-11-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727245 SCV000706942 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing
Invitae RCV000727245 SCV001054085 benign not provided 2018-06-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000501419 SCV001278237 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000727245 SCV001551573 uncertain significance not provided no assertion criteria provided clinical testing The OCA2 p.Gly27Arg variant was identified in 3 of 242 proband chromosomes (frequency: 0.037) from non-hispanic caucasian individuals with oculocutaneous albinism (OCA) (Hutton_2008_PMID:18463683). The variant was also identified in dbSNP (ID: rs61738394) and ClinVar (classified as pathogenic by EGL Genetics, likely pathogenic by Genetic Services Laboratory, University of Chicago and as a VUS by GeneDx). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 491 of 273964 chromosomes (3 homozygous) at a frequency of 0.001792 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 357 of 23176 chromosomes (freq: 0.0154), Ashkenazi Jewish in 85 of 10146 chromosomes (freq: 0.008378), Other in 9 of 7014 chromosomes (freq: 0.001283), Latino in 23 of 35144 chromosomes (freq: 0.000655), European (non-Finnish) in 14 of 123642 chromosomes (freq: 0.000113), East Asian in 1 of 19664 chromosomes (freq: 0.000051), European (Finnish) in 1 of 24704 chromosomes (freq: 0.00004) and South Asian in 1 of 30474 chromosomes (freq: 0.000033). In two Jewish families, two siblings with OCA2 were homozygous for the G27R variant and two siblings with OCA2 were compound heterozygous for the G27R and A481T variants, however the unaffected father was also compound heterozygous for G27R and A481T (Blumenfeld_2012). The p.Gly27 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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