rs121918166

Positions:

• chr15-27985101-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM5 PP5_Very_Strong BP4

The ENST00000354638.8(OCA2):​c.1327G>A​(p.Val443Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00591 in 1,613,948 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V443A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (36 hom.)
• Consequence: OCA2 ENST00000354638.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38 U:1
• Conservation: PhyloP100: 7.14

Genes affected

OCA2 (HGNC:8101): (OCA2 melanosomal transmembrane protein) This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000354638.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27985100-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1516182.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 15-27985101-C-T is Pathogenic according to our data. Variant chr15-27985101-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27985101-C-T is described in Lovd as [Pathogenic]. Variant chr15-27985101-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-27985101-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.035922796). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1327G>A	p.Val443Ile	missense_variant	13/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1327G>A	p.Val443Ile	missense_variant	13/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.1255G>A	p.Val419Ile	missense_variant	12/23	1		ENSP00000261276

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152144 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00305 AC: 762 AN: 250050 Hom.: 3 AF XY: 0.00296 AC XY: 401 AN XY: 135286

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00618 AC: 9032 AN: 1461686 Hom.: 36 Cov.: 34 AF XY: 0.00592 AC XY: 4307 AN XY: 727128

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74440

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00540 Hom.: 8

Bravo AF: 0.00351

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:38 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:18 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS3_Supporting+PM3_VeryStrong+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 04, 2023	PS3, PP3, PM3_Strong, PM6 -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Oct 24, 2023	This sequence variant is a single nucleotide substitution (G>A) at position 1327 of the coding sequence of the OCA2 gene that results in a valine to isoleucine amino acid change at residue 443 of the OCA2 melanosomal transmembrane protein. This residue falls in a lumil loop domain which plays a critical role in OCA2 melanosomal transmembrane protein's function in melanin production (PMID: 25513726). This is a previously reported variant (ClinVar 955) that has been observed in individuals affected by oculocutaneous albinism (PMID: 8302318, 18463683, 32830442, 31233279, 34246199, 31196117) and melanoma (PMID: 32966289, 31233279). This variant is present in 860 of 281442 alleles (0.3056%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this valine to isoleucine amino acid change would be damaging, and the Val443 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant demonstrate impaired protein function leading to reduced/absent melanin production (PMID: 8980282, 25513726). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	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. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 11, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM3,PP3,PP4,PP5,BS2. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Sep 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 24, 1994	- -

not provided Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 30, 2022	PM3, PS3, PP3, PM5, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	OCA2: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Nov 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

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. -

OCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2024

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. -

Albinism or congenital nystagmus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

NHS Central & South Genomic Laboratory Hub

Jul 01, 2024

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 22, 2020

ACMG classification criteria: PS3, PS4, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.036	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.7	.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.82
MVP		0.91
MPC		0.44
ClinPred		0.11	T
GERP RS		5.2
Varity_R		0.46
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918166; hg19: chr15-28230247; COSMIC: COSV62340961;