ClinVar Genomic variation as it relates to human health
NM_000275.3(OCA2):c.2020C>G (p.Leu674Val)
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000275.3(OCA2):c.2020C>G (p.Leu674Val)
Variation ID: 194918 Accession: VCV000194918.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q13.1 15: 27926186 (GRCh38) [ NCBI UCSC ] 15: 28171332 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 15, 2018 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000275.3:c.2020C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000266.2:p.Leu674Val missense NM_001300984.2:c.1948C>G NP_001287913.1:p.Leu650Val missense NC_000015.10:g.27926186G>C NC_000015.9:g.28171332G>C NG_009846.1:g.178127C>G - Protein change
- L674V, L650V
- Other names
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- Canonical SPDI
- NC_000015.10:27926185:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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0.00100 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00032
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1267 | 1575 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000175395.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2016 | RCV000624462.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2019 | RCV001078137.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 15, 2018 | RCV001818421.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 22, 2022 | RCV001797661.6 |
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
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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
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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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Uncertain significance
(Nov 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000226870.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(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
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Genome-Nilou Lab
Accession: SCV002039754.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Uncertain significance
(Jun 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069200.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521571.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.032%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.032%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV000194918 / PMID: 23010199). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Albinism (present) , Ocular albinism (present) , Nystagmus (present) , Rotary nystagmus (present) , Photophobia (present) , Cutaneous photosensitivity (present) , Red hair (present) , … (more)
Albinism (present) , Ocular albinism (present) , Nystagmus (present) , Rotary nystagmus (present) , Photophobia (present) , Cutaneous photosensitivity (present) , Red hair (present) , Visual impairment (present) , Involuntary movements (present) , Head tremor (present) (less)
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Pathogenic
(Apr 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741451.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Albinism (present) , Congenital nystagmus (present) , Failure to thrive (present) , 2-3 toe syndactyly (present) , Foveal hypoplasia (present) , Visual impairment (present)
Sex: male
Ethnicity/Population group: Asian
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Uncertain significance
(Mar 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001982337.2
First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in apparent homozygous state in multiple unrelated healthy adult individuals tested … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in apparent homozygous state in multiple unrelated healthy adult individuals tested at GeneDx and in large population cohorts (Lek et al., 2016); Observed with an additional OCA2 variant in patients with hypomorphic albinism in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (also known as p.L650V using alternate nomenclature; Mondal et al., 2012; Norman et al., 2017); Observed in the apparent homozygous state in a patient with features of ocular albinism in the published literature (Mondal et al., 2012); This variant is associated with the following publications: (PMID: 23970088, 23010199, 28667292) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-positive oculocutaneous albinism
Affected status: yes
Allele origin:
paternal
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004021946.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Likely pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020185.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism
Congenital nystagmus Respiratory tract infection Diarrhea Motor delay, mild Febrile seizures (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology
Accession: SCV001190097.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Comment:
The c.2020C>G variant is not present in publicly available databases like Exome Variant Server (EVS) however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome … (more)
The c.2020C>G variant is not present in publicly available databases like Exome Variant Server (EVS) however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a low minor allele frequency (MAF<0.001) including one homozygote. The variant is present in our in-house exome database in heterozygous state (MAF~0.004). The variant was earlier reported to ClinVar (Accession ID: VCV000194918.1) with conflicting interpretation of pathogenicity (likely pathogenic/uncertain significance). In-silico pathogenicity prediction programs Like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant as likely deleterious, however there are no functional studies performed earlier to prove this. Due to lack of enough evidence and also considering the additional phenotypes observed in this patient along with oculocutaneous albinism and nystagmus, the variant as has been classified as uncertain significance as per ACMG guidelines. (less)
Age: 0-9 years
Sex: male
Geographic origin: India
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001536002.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 674 of the OCA2 protein (p.Leu674Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 674 of the OCA2 protein (p.Leu674Val). This variant is present in population databases (rs371412500, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 23010199, 28667292; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1948C>G. ClinVar contains an entry for this variant (Variation ID: 194918). 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) performed at Invitae indicates that this missense variant is not expected to disrupt OCA2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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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 |
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Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B). | Norman CS | Scientific reports | 2017 | PMID: 28667292 |
Molecular basis of albinism in India: evaluation of seven potential candidate genes and some new findings. | Mondal M | Gene | 2012 | PMID: 23010199 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OCA2 | - | - | - | - |
- | - | - | - | DOI: 10.1016/j.gene.2012.09.012 |
Text-mined citations for rs371412500 ...
HelpRecord last updated Mar 17, 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.