ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.[1205G>A;575C>A]
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
NM_000372.5(TYR):c.[1205G>A;575C>A]
- Other names
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- Functional consequence
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- Links
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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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TYR | - | - |
GRCh38 GRCh37 |
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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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2023 | RCV002226432.5 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2022 | RCV003150831.6 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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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Likely pathogenic
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-negative oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839046.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
c.[575C>A;1205G>A] is a complex allele containing two TYR variants (rs1042602; rs1126809) that are located on the same chromosome (in cis). Each variant has an entry … (more)
c.[575C>A;1205G>A] is a complex allele containing two TYR variants (rs1042602; rs1126809) that are located on the same chromosome (in cis). Each variant has an entry in ClinVar. The pathogenicity of these individual variants and their contribution to the OCA1 phenotype has been debated. Previously described as benign polymorphisms due to their frequency in the general population (25 and 18% respectively), recent evidence supports pathogenicity of these two variants when they occur on the same haplotype and are co-inherited with a pathogenic TYR variant on the opposite chromosome (in trans). The resulting hypomorphic allele, p.[Ser192Tyr;Arg402Gln], exhibits an additive thermosensitive decrease in tyrosinase enzyme activity compared to each variant individually. This variant likely occurs in trans with a known pathogenic TYR variant. Based on the available evidence, we consider this complex allele, which combines c.575C>A and c.1205G>A, to be likely pathogenic. (less)
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Likely pathogenic
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1B
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839047.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
c.[575C>A;1205G>A] is a complex allele containing two TYR variants (rs1042602; rs1126809) that are located on the same chromosome (in cis). Each variant has an entry … (more)
c.[575C>A;1205G>A] is a complex allele containing two TYR variants (rs1042602; rs1126809) that are located on the same chromosome (in cis). Each variant has an entry in ClinVar. The pathogenicity of these individual variants and their contribution to the OCA1 phenotype has been debated. Previously described as benign polymorphisms due to their frequency in the general population (25 and 18% respectively), recent evidence supports pathogenicity of these two variants when they occur on the same haplotype and are co-inherited with a pathogenic TYR variant on the opposite chromosome (in trans). The resulting hypomorphic allele, p.[Ser192Tyr;Arg402Gln], exhibits an additive thermosensitive decrease in tyrosinase enzyme activity compared to each variant individually. This variant likely occurs in trans with a known pathogenic TYR variant. Based on the available evidence, we consider this complex allele, which combines c.575C>A and c.1205G>A, to be likely pathogenic. (less)
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Likely pathogenic
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003922023.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
Combination of these two variants appears to be a hypomorphic allele These variants were observed in compound heterozygosity with c.1467dup variant
Method: Exome sequencing
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-negative oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004174896.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
These two variants are both very common in the general population, with c.575C>A (p.Ser192Tyr) being documented in 45% of alleles in individuals of Ashkenazi Jewish … (more)
These two variants are both very common in the general population, with c.575C>A (p.Ser192Tyr) being documented in 45% of alleles in individuals of Ashkenazi Jewish descent (http://gnomad.broadinstitute.org/variant/11-88911696-C-A) and c.1205G>A (p.Arg402Gln) being documented in 27% of alleles in individuals of European (Non-Finnish) descent. Given the high allele frequencies, including thousands of homozygotes for both variants, these variants are not considered pathogenic individually. However, when these two variants are in cis (present in the same copy of TYR), there is strong evidence that they create a pathogenic allele. Functional and phenotypic studies of the complex allele (p.[Arg402Gln;Ser192Tyr]; commonly referred to as a haplotype in the literature) indicate that the two substitutions have a compound effect on thermal stability of the protein and phenotypic spectrum of the individual (Tripathi et al. 1991. PubMed ID: 1820207; Chaki et al. 2011. PubMed ID: 20861851; Jagirdar et al. 2014. PubMed ID: 24739399). The p.[Arg402Gln;Ser192Tyr] allele is thought to be a recombination of the two individual variant alleles and is reported in ~1-2% of alleles (Jagirdar et al. 2014. PubMed ID: 24739399; Norman et al. 2017. PubMed ID: 28667292). However, this complex allele is enriched (up to 20%) in OCA patients with only one previously identified pathogenic variant in TYR (Lasseaux et al. 2018. PubMed ID: 29345414; Grønskov et al. 2019. PubMed ID: 30679655; Campbell et al. 2019. PubMed ID: 31719542). Given the evidence, we interpret the p.[Arg402Gln;Ser192Tyr] allele as likely pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Oculocutaneous albinism type 1B
Affected status: yes
Allele origin:
inherited
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Rare Disease Group, University of Exeter
Accession: SCV001984756.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
Hypomorphic allele
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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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- | - | - | - | PMID: 16907708 |
- | - | - | - | PMID: 17952075 |
- | - | - | - | PMID: 17999355 |
- | - | - | - | PMID: 1899321 |
- | - | - | - | PMID: 26165494 |
- | - | - | - | PMID: 28378818 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
- | - | - | - | PMID: 20301345 |
King, R. A., Townsend, D., Oetting, W. S., Spritz, R. A. An unusual pigment pattern in type I oculocutaneous albinism (OCA) resulting from a temperature-sensitive enzyme. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A8, 1989. | - | - | - | - |
- | - | - | - | PMID: 10766867 |
- | - | - | - | PMID: 1429711 |
- | - | - | - | PMID: 17952075 |
- | - | - | - | PMID: 1820207 |
- | - | - | - | PMID: 18326704 |
- | - | - | - | PMID: 18488027 |
- | - | - | - | PMID: 18488028 |
- | - | - | - | PMID: 18925668 |
- | - | - | - | PMID: 19208379 |
- | - | - | - | PMID: 19533789 |
- | - | - | - | PMID: 21541274 |
- | - | - | - | PMID: 23504663 |
- | - | - | - | PMID: 25216246 |
- | - | - | - | PMID: 30472657 |
- | - | - | - | PMID: 35803923 |
- | - | - | - | PMID: 666627 |
- | - | - | - | PMID: 7704033 |
- | - | - | - | PMID: 9158138 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
- | - | - | - | PMID: 20301345 |
- | - | - | - | PMID: 28667292 |
- | - | - | - | PMID: 35027574 |
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Text-mined citations for this variant ...
HelpRecord last updated Jun 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.