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

gnomAD frequency: 0.00350  dbSNP: rs121918166

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000310636	SCV000225767	pathogenic	not provided	2017-03-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000001006	SCV000248365	pathogenic	Tyrosinase-positive oculocutaneous albinism	2015-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000310636	SCV000329644	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant disrupts ion conductance, which is required for melanin production (Bellono et al., 2014); This variant is associated with the following publications: (PMID: 8302318, 27468418, 27140606, 20019752, 25513726, 23744323, 18463683, 26474496, 27231233, 18326704, 28667292, 30487145, 30665703, 30414346, 31719542, 31206972, 28976636, 31233279, 31980526, 31589614, 32966289, 34426522)
Illumina Laboratory Services, 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000001006	SCV000584106	pathogenic	Tyrosinase-positive oculocutaneous albinism	2014-09-11	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000477815	SCV000611223	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2017-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623104	SCV000742020	pathogenic	Inborn genetic diseases	2023-06-30	criteria provided, single submitter	clinical testing	The c.1327G>A (p.V443I) alteration is located in exon 13 (coding exon 12) of the OCA2 gene. This alteration results from a G to A substitution at nucleotide position 1327, causing the valine (V) at amino acid position 443 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.306% (860/281442) total alleles studied. The highest observed frequency was 0.51% (653/128140) of European (non-Finnish) alleles. The OCA2 c.1327G>A (p.V443I) alteration is one of the most common pathogenic variants in OCA2 and has been identified in homozygous state and in trans with other pathogenic variants in multiple unrelated individuals with oculocutaneous albinism type II (Lee, 1994; Passmore, 1999; Oetting, 2005; Hutton, 2008; Marti, 2018; Wei, 2022). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that transfection of the p.V433I mutant protein into immortalized melanocytes that are null for OCA2 was unable to correct for deficient melanin biosynthesis and hypopigmentation compared to cells transfected with wild-type protein (Sviderskaya, 1997). Additionally, Bellono (2014) showed that OCA2 mediates chloride-selective anion conductance and although mutant V443I localization remains intact, it had significantly reduced amplitudes compared to wild-type OCA2. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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, http://gnomad.broadinstitute.org; 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.
Mendelics	RCV000001006	SCV001139535	pathogenic	Tyrosinase-positive oculocutaneous albinism	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000310636	SCV001250101	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	OCA2: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000310636	SCV001586228	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 443 of the OCA2 protein (p.Val443Ile). This variant is present in population databases (rs121918166, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 8302318, 17960121, 20301410, 28976636, 29345414). 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: 955). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OCA2 protein function. Experimental studies have shown that this missense change affects OCA2 function (PMID: 8980282, 25513726). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000310636	SCV002020569	pathogenic	not provided	2022-04-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000001006	SCV002039331	pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000310636	SCV002049421	pathogenic	not provided	2021-08-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251850	SCV002523557	pathogenic	See cases	2020-02-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001006	SCV002572351	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-08-26	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1327G>A (p.Val443Ile) results in a conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 250050 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allow conclusions about variant significance. c.1327G>A has been widely reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Oculocutaneous Albinism (example, Lasseaux_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bellono_2014). The most pronounced variant effect results in near abolishment of normal ion channel activity as measured by OCA2-mediated chloride current measurements in-vitro. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as pathogenic (n=15, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000001006	SCV002581646	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-07-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001006	SCV002768880	pathogenic	Tyrosinase-positive oculocutaneous albinism	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism (MIM#203200) and oculocutaneous albinism, type II (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 24518832; OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (852 heterozygotes, 4 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated citrate transporter domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. p.(Val443Ile) is a well-reported variant associated with oculocutaneous albinism and has previously been reported in more than ten individuals with a clinical diagnosis of oculocutaneous albinism, in homozygous and compound heterozygous state (PMID: 31196117, PMID: 18463683) (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000001006	SCV003804566	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000310636	SCV004026110	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	PM3, PS3, PP3, PM5, PS4
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000001006	SCV004177044	pathogenic	Tyrosinase-positive oculocutaneous albinism	2023-09-22	criteria provided, single submitter	clinical testing	The OCA2 c.1327G>A (p.Val443Ile) variant has been reported in the homozygous and compound heterozygous state in many individuals affected with oculocutaneous albinism and is reported to be the most common pathogenic OCA2 variant in individuals of European ancestry (Andersen JD et al., PMID: 27468418; Gao J et al., PMID: 28451379; Gargiulo A et al., PMID: 20861488; Hutton SM et al., PMID: 18463683; Oetting WS et al., PMID: 15712365; Wolfson Y et al., PMID: 26474496). This variant has been reported in the ClinVar database as a germline pathogenic variant by more than 20 submitters. The highest population minor allele frequency in the genome aggregation database (v.2.1.1) is 0.5% in the European population which is consistent with the carrier frequency of oculocutaneous albinism (Grønskov K et al., PMID: 17980020). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to OCA2 function. In support of this prediction, functional studies show the variant reduced protein function and altered protein localization (Bellono NW et al., PMID: 25513726; Sviderskaya EV et al., PMID: 8980282). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Baylor Genetics	RCV003466772	SCV004208965	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-30	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000001006	SCV004244523	pathogenic	Tyrosinase-positive oculocutaneous albinism	2023-10-04	criteria provided, single submitter	clinical testing	PS3, PP3, PM3_Strong, PM6
NHS Central & South Genomic Laboratory Hub	RCV004584136	SCV005068211	pathogenic	Albinism or congenital nystagmus	2024-07-01	criteria provided, single submitter	clinical testing
OMIM	RCV000001006	SCV000021156	pathogenic	Tyrosinase-positive oculocutaneous albinism	1994-02-24	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477815	SCV000536763	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2014-11-13	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000001006	SCV001142446	pathogenic	Tyrosinase-positive oculocutaneous albinism	2020-01-06	no assertion criteria provided	curation	NM_000275.2:c.1327G>A in the OCA2 gene has an allele frequency of 0.005 in European (no Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that the V443I variant disrupts ion conductance, which is required for melanin production (PMID: 27231233). It was detected in multiple individuals with autosomal recessive Oculocutaneous albinism, two homozygous for this variant, compound heterozygous with c.2228C>T, c.1465A>G, Deletion 15q11.2-q13.1, repectively (PMID: 18463683). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_VeryStrong; PS3; PP4.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000001006	SCV001370164	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2016-01-01	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM3,PP3,PP4,PP5,BS2.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000310636	SCV001553011	pathogenic	not provided		no assertion criteria provided	clinical testing	The OCA2 p.Val419Ile variant (alias: p.Val443Ile) is a well-known variant associated with Oculocutaneous Albinism (OCA). The variant was identified in dbSNP (ID: rs121918166) and was classified as pathogenic in ClinVar by nine submitters (8x pathogenic and 1x likely pathogenic). The associated conditions are: Tyrosinase-positive oculocutaneous albinism, Skin/hair/eye pigmentation, and Oculocutaneous albinism. The variant was also identified in LOVD 3.0 but not Cosmic. The variant was identified in control databases in 860 of 281442 chromosomes (4 homozygous) at a frequency of 0.003056 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: European (non-Finnish) in 653 of 128140 chromosomes (freq: 0.005096), Ashkenazi Jewish in 38 of 10324 chromosomes (freq: 0.003681), Other in 24 of 7196 chromosomes (freq: 0.003335), Latino in 71 of 35394 chromosomes (freq: 0.002006), African in 40 of 24840 chromosomes (freq: 0.00161), European (Finnish) in 23 of 25024 chromosomes (freq: 0.000919), East Asian in 7 of 19928 chromosomes (freq: 0.000351), and South Asian in 4 of 30596 chromosomes (freq: 0.000131). The protein product of OCA2 is known as the P protein which is a transmembrane protein found in the melanosomal membrane. A functional study expressing the OCA2 mutant cDNA containing p.Val443Ile in mouse melanocytes showed decreased melanin production compared to wildtype (Sviderskaya_1997_PMID: 8980282). Another functional study also 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 (Bellano_2014_PMID: 25513726). The variant has been identified in individuals or families with Oculocutaneous Albinism (OCA) (Zhang_2013_PMID: 23744323, Lee_1994_PMID: 8302318, Wei_2016_PMID: 26165494, and Gargiulo_2011_PMID: 20861488). The p.Val443Ile variant has also been implicated in hair and eye colour variation (Morgan_2018_PMID: 30531825; Anderson_2016_PMID: 27468418). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Val419 residue is conserved in mammals however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Genomics England Pilot Project, Genomics England	RCV000001006	SCV001760341	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000310636	SCV001809014	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000310636	SCV001918379	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000310636	SCV001956693	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000310636	SCV001973829	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000310636	SCV002036843	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000001006	SCV004099434	pathogenic	Tyrosinase-positive oculocutaneous albinism	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415611	SCV004109354	pathogenic	OCA2-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The OCA2 c.1327G>A variant is predicted to result in the amino acid substitution p.Val443Ile. This variant has been reported to be causative for autosomal recessive oculocutaneous albinism when present with a second pathogenic variant in OCA2 (see for example, Lee et al. 1994. PubMed ID: 8302318; Preising et al. 2007. PubMed ID: 17960121; Marti et al. 2018. PubMed ID: 28976636). The global allele frequency of this variant is 0.31% including 4 homozygous individuals, which is higher than expected for a pathogenic variant; however, this variant has been well documented in the literature in individuals with oculocutaneous albinism, and several independent submitters to the ClinVar database have classified this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/955/). Given the evidence, we interpret this variant as pathogenic.