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

gnomAD frequency: 0.00532  dbSNP: rs61738394

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727245	SCV000589529	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Observed with p.(L440F) on the same allele (in cis) in multiple unrelated individuals referred for genetic testing at GeneDx; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15173252, 23891399, 18463683, 15712365, 20981092, 23504663, 19626598, 18326704, 23824587, 9259203, 31636960, 27887888)
Genetic Services Laboratory, University of Chicago	RCV001172458	SCV000596151	uncertain significance	not specified	2017-11-06	criteria provided, single submitter	clinical testing
Invitae	RCV000727245	SCV001054085	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Genome-Nilou Lab	RCV000501419	SCV002040136	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403148	SCV004118780	uncertain significance	OCA2-related disorder	2023-05-01	criteria provided, single submitter	clinical testing	The OCA2 c.79G>A variant is predicted to result in the amino acid substitution p.Gly27Arg. This variant has been reported several times in individuals with oculocutaneous albinism (Spritz et al. 1997. PubMed ID: 9259203; Garrison et al. 2004. PubMed ID: 15173252; Hutton and Spritz. 2008. PubMed ID: 18463683). However, this variant is reported in 1.5% of alleles in individuals of African descent in gnomAD, including at least three homozygous individuals (http://gnomad.broadinstitute.org/variant/15-28326942-C-T). This variant has conflicting interpretations in ClinVar, ranging from pathogenic to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/431946). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000727245	SCV004131471	benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	OCA2: BP4, BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001172458	SCV004241991	benign	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 1612778 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in OCA2 causing Oculocutaneous Albinism phenotype (0.0043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.79G>A has been reported in the literature in individuals affected with Oculocutaneous Albinism without strong evidence for causality, as they were either not comprehensively genotyped, or harbored other putatively pathogenic variants in OCA2 and/or other Oculocutaneous Albinism-related genes (e.g. Spritz_1997, Oetting_2005, Hutton_2008a, Hutton_2008b). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. 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: 18326704, 18463683, 15712365, 9259203). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Five submitters classified the variant as uncertain significance, two classified it as benign, and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000727245	SCV000706942	pathogenic	not provided	2017-04-05	flagged submission	clinical testing
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.