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

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Interpretation:
Conflicting interpretations of pathogenicity​

Pathogenic(11);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
21 (Most recent: Sep 30, 2021)
Last evaluated:
May 1, 2021
Accession:
VCV000000955.23
Variation ID:
955
Description:
single nucleotide variant
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NM_000275.3(OCA2):c.1327G>A (p.Val443Ile)

Allele ID
15994
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q13.1
Genomic location
15: 27985101 (GRCh38) GRCh38 UCSC
15: 28230247 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
Q04671:p.Val443Ile
NC_000015.10:g.27985101C>T
NC_000015.9:g.28230247C>T
... more HGVS
Protein change
V443I, V419I
Other names
-
Canonical SPDI
NC_000015.10:27985100:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00080 (T)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00375
1000 Genomes Project 0.00080
Exome Aggregation Consortium (ExAC) 0.00285
The Genome Aggregation Database (gnomAD), exomes 0.00305
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00492
The Genome Aggregation Database (gnomAD) 0.00312
Links
ClinGen: CA251634
UniProtKB: Q04671#VAR_006132
OMIM: 611409.0004
dbSNP: rs121918166
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 9 criteria provided, multiple submitters, no conflicts May 1, 2021 RCV000310636.12
Pathogenic 2 criteria provided, single submitter May 18, 2017 RCV000477815.4
Pathogenic 1 criteria provided, single submitter Nov 29, 2016 RCV000623104.1
Conflicting interpretations of pathogenicity 9 criteria provided, conflicting interpretations May 28, 2019 RCV000001006.15

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
OCA2 - - GRCh38
GRCh38
GRCh38
GRCh37
329 645

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Mar 02, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000225767.5
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (4)
Other databases
http://www.egl-eurofins.com/emvc…
http://www.ncbi.nlm.nih.gov/book…
Pathogenic
(Nov 29, 2016)
criteria provided, single submitter
Method: clinical testing
Inborn genetic diseases
Allele origin: germline
Ambry Genetics
Accession: SCV000742020.2
Submitted: (Oct 09, 2020)
Evidence details
Publications
PubMed (8)
Pathogenic
(Apr 17, 2015)
criteria provided, single submitter
Method: clinical testing
Albinism, oculocutaneous, type II
Allele origin: germline
Genetic Services Laboratory, University of Chicago
Accession: SCV000248365.1
Submitted: (Sep 15, 2015)
Evidence details
Pathogenic
(Apr 05, 2019)
criteria provided, single submitter
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000390147.3
Submitted: (Apr 05, 2019)
Evidence details
Publications
PubMed (8)
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)
Pathogenic
(Feb 06, 2018)
criteria provided, single submitter
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
(Autosomal recessive inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000966900.1
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (14)
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)
Pathogenic
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
Allele origin: unknown
Mendelics
Accession: SCV001139535.1
Submitted: (Oct 22, 2019)
Evidence details
Pathogenic
(Oct 26, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV001586228.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change replaces valine with isoleucine at codon 443 of the OCA2 protein (p.Val443Ile). The valine residue is highly conserved and there is a … (more)
Pathogenic
(Sep 11, 2014)
criteria provided, single submitter
Method: research
Tyrosinase-positive oculocutaneous albinism
Allele origin: paternal
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584106.1
Submitted: (Jul 06, 2017)
Evidence details
Pathogenic
(May 18, 2017)
criteria provided, single submitter
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
Skin/hair/eye pigmentation, variation in, 1
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000611223.1
Submitted: (May 23, 2017)
Evidence details
Pathogenic
(Jan 10, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000329644.6
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The V443I pathogenic variant in the OCA2 gene has been reported previously multiple times in both the homozygous state and in trans with another OCA2 … (more)
Uncertain significance
(Jan 01, 2016)
criteria provided, single submitter
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
Allele origin: unknown
Centre for Mendelian Genomics,University Medical Centre Ljubljana
Accession: SCV001370164.2
Submitted: (Nov 24, 2020)
Evidence details
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM3,PP3,PP4,PP5,BS2.
Pathogenic
(May 01, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001250101.6
Submitted: (Jul 04, 2021)
Evidence details
Likely pathogenic
(Nov 13, 2014)
no assertion criteria provided
Method: research
Skin/hair/eye pigmentation, variation in, 1
Tyrosinase-positive oculocutaneous albinism
Allele origin: germline
Division of Human Genetics,Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536763.1
Submitted: (Jan 23, 2017)
Evidence details
Publications
PubMed (3)
Pathogenic
(Feb 24, 1994)
no assertion criteria provided
Method: literature only
ALBINISM, OCULOCUTANEOUS, TYPE II
Allele origin: germline
OMIM
Accession: SCV000021156.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (2)
Pathogenic
(Jan 06, 2020)
no assertion criteria provided
Method: curation
Albinism, oculocutaneous, type II
Allele origin: germline
Reproductive Health Research and Development,BGI Genomics
Accession: SCV001142446.1
Submitted: (Jan 06, 2020)
Evidence details
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)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
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
Submitted: (Mar 31, 2021)
Evidence details
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)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809014.1
Submitted: (Aug 24, 2021)
Evidence details
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Human Genetics - Radboudumc,Radboudumc
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956693.1
Submitted: (Sep 30, 2021)
Evidence details
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
Tyrosinase-positive oculocutaneous albinism
Allele origin: germline
Genomics England Pilot Project,Genomics England
Accession: SCV001760341.1
Submitted: (Jul 15, 2021)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Clinical Genetics,Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918379.1
Submitted: (Sep 23, 2021)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
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
Submitted: (Sep 21, 2021)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
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 <i>OCA2</i> 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
[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 Lewis RA - 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/ - - - -

Text-mined citations for rs121918166...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 07, 2021