ClinVar Genomic variation as it relates to human health
NM_000275.3(OCA2):c.1327G>A (p.Val443Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000275.3(OCA2):c.1327G>A (p.Val443Ile)
Variation ID: 955 Accession: VCV000000955.83
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q13.1 15: 27985101 (GRCh38) [ NCBI UCSC ] 15: 28230247 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 1, 2015 Oct 8, 2024 Jul 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000275.3:c.1327G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000266.2:p.Val443Ile missense NM_001300984.2:c.1255G>A NP_001287913.1:p.Val419Ile missense NC_000015.10:g.27985101C>T NC_000015.9:g.28230247C>T NG_009846.1:g.119212G>A Q04671:p.Val443Ile - Protein change
- V443I, V419I
- Other names
- -
- Canonical SPDI
- NC_000015.10:27985100:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
Exome Aggregation Consortium (ExAC) 0.00285
The Genome Aggregation Database (gnomAD), exomes 0.00305
The Genome Aggregation Database (gnomAD) 0.00350
Trans-Omics for Precision Medicine (TOPMed) 0.00351
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00492
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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OCA2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh37 |
1308 | 1617 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (17) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV000001006.47 | |
Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000310636.55 | |
Pathogenic (2) |
criteria provided, single submitter
|
May 18, 2017 | RCV000477815.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 30, 2023 | RCV000623104.13 | |
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 22, 2020 | RCV002251850.9 |
OCA2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2024 | RCV003415611.6 |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2024 | RCV003466772.2 | |
Albinism or congenital nystagmus
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Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2024 | RCV004584136.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Albinism, oculocutaneous, type II
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248365.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Sep 11, 2014)
|
criteria provided, single submitter
Method: research
|
Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
paternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584106.1 First in ClinVar: Jul 29, 2017 Last updated: Jul 29, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611223.1
First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
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Pathogenic
(Feb 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966900.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139535.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002039331.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
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Pathogenic
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049421.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
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Pathogenic
(Aug 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572351.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329644.9
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026110.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PM3, PS3, PP3, PM5, PS4
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Pathogenic
(Sep 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004177044.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020569.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001586228.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Albinism or congenital nystagmus
Affected status: yes
Allele origin:
germline
|
NHS Central & South Genomic Laboratory Hub
Accession: SCV005068211.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
|
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Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768880.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Mar 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225767.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 17
Sex: mixed
|
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Pathogenic
(Apr 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000390147.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523557.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM3
Clinical Features:
Visual loss (present) , Retinal degeneration (present) , Abnormal optic nerve morphology (present)
Geographic origin: Brazil
|
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Pathogenic
(Jul 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581646.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_STR, PS3_MOD, PS4_MOD, PM2_SUP, PP3
|
Number of individuals with the variant: 5
Sex: male
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV003804566.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
|
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Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244523.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PP3, PM3_Strong, PM6
|
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Pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742020.6
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208965.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250101.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Comment:
OCA2: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Number of individuals with the variant: 14
|
|
Likely pathogenic
(Nov 13, 2014)
|
no assertion criteria provided
Method: research
|
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
Tyrosinase-positive oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536763.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809014.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956693.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973829.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036843.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Feb 24, 1994)
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no assertion criteria provided
Method: literature only
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ALBINISM, OCULOCUTANEOUS, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021156.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 28, 2023 |
Comment on evidence:
In a 4-year-old boy of northern European ancestry with typical type II oculocutaneous albinism (OCA2; 203200), Lee et al. (1994) identified compound heterozygosity for 2 … (more)
In a 4-year-old boy of northern European ancestry with typical type II oculocutaneous albinism (OCA2; 203200), Lee et al. (1994) identified compound heterozygosity for 2 mutations in the OCA2 gene: a G-to-A transition, resulting in a val443-to-ile (V443I) substitution inherited from the mother, and a C-to-T transition in exon 22 resulting in a pro743-to-leu (P743L; 611409.0005) substitution inherited from the father. The patient's skin was very lightly pigmented with no apparent tanning ability, and his hair was pale golden yellow. His irides were blue and showed transillumination, and the fundi appeared nonpigmented, with hypoplastic maculae. His corrected visual acuity was 20/100, and he had nystagmus and strabismus. Chromosomal analysis demonstrated mosaicism for 46,XY and 46,XY,dup(15)(q12). The duplication, which occurred in 25% of stimulated peripheral-blood leukocytes, was interpreted as a nonpathologic chromosomal variant (Ludowese et al., 1991). Lee et al. (1994) found the same V443I substitution on the maternally derived chromosome 15 in a 7-year-old boy with typical type II oculocutaneous albinism and Prader-Willi syndrome (PWS; 176270), the latter being due to deletion of 15q11.2-q13.1 derived from the father. The paternal OCA2 gene was deleted in this child. In a mother and 3 of her children in a Czech family with oculocutaneous or ocular albinism, Jedlickova et al. (2023) identified homozygosity or compound heterozygosity for the V443I mutation in the OCA2 gene. The mother and a daughter, who both had oculocutaneous albinism, were compound heterozygous for V443I and a large complex rearrangement in the OCA2 gene, whereas the 2 sons, who had ocular albinism, were homozygous for the V443I substitution. The authors noted that the sons had normal visual acuity with discrete fundus hypopigmentation and foveal hypoplasia, which was only revealed due to the familial investigation; they suggested that these findings supported the notion of V443I as a hypomorphic allele causing only a partial loss of function, thus accounting for the 4 homozygous individuals present in the gnomAD database (v2.1.1). (less)
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Pathogenic
(Oct 30, 2023)
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no assertion criteria provided
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004099434.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Sep 16, 2024)
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no assertion criteria provided
Method: clinical testing
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OCA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109354.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Albinism, oculocutaneous, type II
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142446.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553011.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760341.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918379.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(Jan 01, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370164.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM3,PP3,PP4,PP5,BS2.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
MIR204 n.37C>T variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma. | Jedlickova J | Clinical genetics | 2023 | PMID: 37321975 |
Spectrum Analysis of Albinism Genes in a Large Cohort of Chinese Index Patients. | Wei A | The Journal of investigative dermatology | 2022 | PMID: 34838614 |
Genetic analyses of oculocutaneous albinism types 1 and 2 with four novel mutations. | Yang Q | BMC medical genetics | 2019 | PMID: 31196117 |
Molecular characterization of a series of 990 index patients with albinism. | Lasseaux E | Pigment cell & melanoma research | 2018 | PMID: 29345414 |
Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting. | Marti A | Pigment cell & melanoma research | 2018 | PMID: 28976636 |
Retrospective analysis in oculocutaneous albinism patients for the 2.7 kb deletion in the OCA2 gene revealed a co-segregation of the controversial variant, p.R305W. | Gao J | Cell & bioscience | 2017 | PMID: 28451379 |
Importance of nonsynonymous OCA2 variants in human eye color prediction. | Andersen JD | Molecular genetics & genomic medicine | 2016 | PMID: 27468418 |
A melanosomal two-pore sodium channel regulates pigmentation. | Bellono NW | Scientific reports | 2016 | PMID: 27231233 |
Evidence of macular pigment in the central macula in albinism. | Wolfson Y | Experimental eye research | 2016 | PMID: 26474496 |
Prenatal genotyping of four common oculocutaneous albinism genes in 51 Chinese families. | Wei AH | Journal of genetics and genomics = Yi chuan xue bao | 2015 | PMID: 26165494 |
An intracellular anion channel critical for pigmentation. | Bellono NW | eLife | 2014 | PMID: 25513726 |
Clinical utility gene card for: Oculocutaneous albinism. | Grønskov K | European journal of human genetics : EJHG | 2014 | PMID: 24518832 |
[A de novo mutation of P gene causes oculocutaneous albinism type 2 with prenatal diagnosis]. | Zhang L | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2013 | PMID: 23744323 |
Oculocutaneous Albinism Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301410 |
Molecular and clinical characterization of albinism in a large cohort of Italian patients. | Gargiulo A | Investigative ophthalmology & visual science | 2011 | PMID: 20861488 |
Comprehensive analysis of oculocutaneous albinism among non-Hispanic caucasians shows that OCA1 is the most prevalent OCA type. | Hutton SM | The Journal of investigative dermatology | 2008 | PMID: 18463683 |
Mutation analysis in a family with oculocutaneous albinism manifesting in the same generation of three branches. | Preising MN | Molecular vision | 2007 | PMID: 17960121 |
P gene mutations associated with oculocutaneous albinism type II (OCA2). | Oetting WS | Human mutation | 2005 | PMID: 15712365 |
The spectrum of Familial Mediterranean Fever (FMF) mutations. | Touitou I | European journal of human genetics : EJHG | 2001 | PMID: 11464238 |
Oculocutaneous albinism type 2 with a P gene missense mutation in a patient with Angelman syndrome. | Saitoh S | Journal of medical genetics | 2000 | PMID: 10905897 |
Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population. | Passmore LA | Human genetics | 1999 | PMID: 10987646 |
Complementation of hypopigmentation in p-mutant (pink-eyed dilution) mouse melanocytes by normal human P cDNA, and defective complementation by OCA2 mutant sequences. | Sviderskaya EV | The Journal of investigative dermatology | 1997 | PMID: 8980282 |
Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism. | Lee ST | The New England journal of medicine | 1994 | PMID: 8302318 |
Absence of predictable phenotypic expression in proximal 15q duplications. | Ludowese CJ | Clinical genetics | 1991 | PMID: 1773534 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OCA2 | - | - | - | - |
http://www.ncbi.nlm.nih.gov/books/NBK1232/ | - | - | - | - |
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Text-mined citations for rs121918166 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.