ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.242C>T (p.Pro81Leu)
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
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NM_000372.5(TYR):c.242C>T (p.Pro81Leu)
Variation ID: 3772 Accession: VCV000003772.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.3 11: 89178195 (GRCh38) [ NCBI UCSC ] 11: 88911363 (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 Feb 20, 2014 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000372.5:c.242C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000363.1:p.Pro81Leu missense NC_000011.10:g.89178195C>T NC_000011.9:g.88911363C>T NG_008748.1:g.5324C>T P14679:p.Pro81Leu - Protein change
- P81L
- Other names
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- Canonical SPDI
- NC_000011.10:89178194:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD) 0.00018
Trans-Omics for Precision Medicine (TOPMed) 0.00018
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
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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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TYR | - | - |
GRCh38 GRCh37 |
656 | 677 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000003970.18 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000085939.15 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jan 1, 2015 | RCV000505170.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 3, 2023 | RCV000623980.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 28, 2017 | RCV000599844.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2019 | RCV001249700.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 4, 2021 | RCV002496249.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV003387499.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003466799.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003993735.1 |
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
(Feb 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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Albinism, oculocutaneous, type IA
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597783.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Pathogenic
(Mar 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713082.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Pro81Leu (NM_000372.4 c.242C>T) variant in TYR has been reported in 4 hete rozygous, 1 homozygous and 7 compound heterozygous individuals with Oculocutaneo us albinism … (more)
The p.Pro81Leu (NM_000372.4 c.242C>T) variant in TYR has been reported in 4 hete rozygous, 1 homozygous and 7 compound heterozygous individuals with Oculocutaneo us albinism type 1 related disorders (OCA1) (Giebel 1990, King 2003, Opitz 2004, Hutton 2008, Rooryck 2008), segregated in at least 8 family members in 2 famili es (Giebel 2003), and has been reported at pathogenic in ClinVar (Variation ID#3 772). This variant has been identified in 0.015% (10/66458) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs28940876). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, this variant meets criteria to be classified as pathogenic for OCA 1 in an autosomal recessive manner based upon biallelic case observations and se gregation in affected individuals. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812507.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in TYR is predicted to replace proline with leucine at codon 81, p.(Pro81Leu). The proline residue is highly conserved (98/98 vertebrates, UCSC), … (more)
This sequence change in TYR is predicted to replace proline with leucine at codon 81, p.(Pro81Leu). The proline residue is highly conserved (98/98 vertebrates, UCSC), and is located in the lumenal melanosome domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.02% (22/128,894 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is a commonly reported pathogenic variant and has been detected in multiple individuals with oculocutaneous albinism in the homozygous state and compound heterozygous with a second pathogenic variant in the gene (PMID: 8434585, 28451379). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP3. (less)
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Pathogenic
(Apr 03, 2015)
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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: SCV000224203.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-negative oculocutaneous albinism
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001821924.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(May 04, 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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Mendelics
Accession: SCV002519927.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Nov 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinase-negative oculocutaneous albinism
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Oculocutaneous albinism type 1B
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809417.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1B
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001423722.2
First in ClinVar: Jul 25, 2020 Last updated: Mar 04, 2023 |
Comment:
Across a selection of the available literature, the TYR c.242C>T (p.Pro81Leu) missense variant has been identified a total of 31 individuals with oculocutaneous albinism type … (more)
Across a selection of the available literature, the TYR c.242C>T (p.Pro81Leu) missense variant has been identified a total of 31 individuals with oculocutaneous albinism type 1, including in three individuals in a homozygous state, in seven individuals in a compound heterozygous state, and in 14 individuals in an assumed compund heterozygous state (Oetting et al. 1991; Giebel et al. 1991; Hutton et al. 2008; King et al. 2013; Goa et al. 2017). The p.Pro81Leu variant was absent from 33 control subjects but is reported at a frequency of 0.000171 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the application of the ACMG criteria, the p.Pro81Leu variant is classified as pathogenic for oculocutaneous albinism type 1. (less)
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Pathogenic
(Sep 26, 2023)
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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: SCV000491312.3
First in ClinVar: Feb 20, 2014 Last updated: Oct 05, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10987646, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10987646, 28451379, 1903591, 13680365, 18326704, 1970634, 31233279, 30609409, 31589614, 32581362, 33808351, 8434585, 37327787, 29345414, 34662886) (less)
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Pathogenic
(Jul 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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TYR-related disorder
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099254.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PM2, PM3_VeryStrong, PP1, PP3
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004207536.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 29, 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: SCV002189499.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the TYR protein (p.Pro81Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the TYR protein (p.Pro81Leu). This variant is present in population databases (rs28940876, gnomAD 0.02%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1970634, 8434585, 10987646, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3772). 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 expected to disrupt TYR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741319.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.242C>T (p.P81L) alteration is located in exon 1 (coding exon 1) of the TYR gene. This alteration results from a C to T substitution … (more)
The c.242C>T (p.P81L) alteration is located in exon 1 (coding exon 1) of the TYR gene. This alteration results from a C to T substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.009% (26/282452) total alleles studied. The highest observed frequency was 0.017% (22/128894) of European (non-Finnish) alleles. This variant has been identified homozygous and likely in trans with a TYR second variant in multiple individuals diagnosed with oculocutaneous albinism (Hutton, 2008; Gao, 2017), as well as in a three individuals from a large family (Giebel, 1990). Another alteration at the same codon, c.241C>T (p.P81S), has been described in one individual with oculocutaneous albinism (King, 2003). This amino acid position is highly conserved in available vertebrate species. 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
(Jul 01, 1991)
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no assertion criteria provided
Method: literature only
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ALBINISM, OCULOCUTANEOUS, TYPE IB
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024135.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
Oculocutaneous Albinism, Type 1B In a patient with 'yellow' OCA (OCA1B; 606952), Spritz et al. (1989) identified a pro81-to-leu (P81L) substitution that was predicted to … (more)
Oculocutaneous Albinism, Type 1B In a patient with 'yellow' OCA (OCA1B; 606952), Spritz et al. (1989) identified a pro81-to-leu (P81L) substitution that was predicted to interfere with the normal folding of the tyrosinase polypeptide. Oculocutaneous Albinism, Type 1A In 6 of 30 unrelated patients with a tyrosinase-negative (type IA) oculocutaneous albinism (OCA1A; 203100), Giebel et al. (1990) observed a CCT-to-CTT change in codon 81 resulting in a substitution of leucine for proline. The codon 81 substitution abolished an HaeIII restriction site within exon 1, thus permitting rapid screening for the substitution by PCR amplification of exon 1 followed by HaeIII cleavage. Giebel et al. (1990) detected the codon 81 mutation in 4 of 15 independently ascertained type I OCA probands; of their 30 OCA tyrosinase alleles, 6 contained the codon 81 mutation, yielding an overall frequency of 0.2 for this allele among these type I OCA probands. Giebel et al. (1991) found the pro81-to-leu mutation in compound heterozygosity in a family with type IB OCA. The other allele was the val275-to-phe mutation (606933.0007). (less)
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Likely pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Albinism
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598734.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000118082.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_TYR:c.242C>T
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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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Molecular characterization of a series of 990 index patients with albinism. | Lasseaux E | Pigment cell & melanoma research | 2018 | PMID: 29345414 |
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 |
Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1-4 genes and practical aspects. | Rooryck C | Pigment cell & melanoma research | 2008 | PMID: 18821858 |
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 |
A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. | Hutton SM | Investigative ophthalmology & visual science | 2008 | PMID: 18326704 |
Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism. | Opitz S | Human mutation | 2004 | PMID: 15146472 |
Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. | King RA | Human genetics | 2003 | PMID: 13680365 |
Oculocutaneous albinism type 1: the last 100 years. | Oetting WS | Pigment cell research | 2003 | PMID: 12753405 |
Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population. | Passmore LA | Human genetics | 1999 | PMID: 10987646 |
Molecular genetics of oculocutaneous albinism. | Spritz RA | Human molecular genetics | 1994 | PMID: 7849740 |
A frequent tyrosinase gene mutation associated with type I-A (tyrosinase-negative) oculocutaneous albinism in Puerto Rico. | Oetting WS | American journal of human genetics | 1993 | PMID: 8434585 |
Tyrosinase gene mutations associated with type IB ("yellow") oculocutaneous albinism. | Giebel LB | American journal of human genetics | 1991 | PMID: 1903591 |
A nonsense mutation in the tyrosinase gene of Afghan patients with tyrosinase negative (type IA) oculocutaneous albinism. | Giebel LB | Journal of medical genetics | 1991 | PMID: 1832718 |
A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous albinism. | Giebel LB | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 1970634 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
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Text-mined citations for rs28940876 ...
HelpRecord last updated May 01, 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.