ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.1217C>T (p.Pro406Leu)
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_000372.5(TYR):c.1217C>T (p.Pro406Leu)
Variation ID: 3777 Accession: VCV000003777.87
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q14.3 11: 89284805 (GRCh38) [ NCBI UCSC ] 11: 89017973 (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 Apr 4, 2013 May 12, 2024 Apr 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000372.5:c.1217C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000363.1:p.Pro406Leu missense NC_000011.10:g.89284805C>T NC_000011.9:g.89017973C>T NG_008748.1:g.111934C>T P14679:p.Pro406Leu - Protein change
- P406L
- Other names
- -
- Canonical SPDI
- NC_000011.10:89284804:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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.
-
0.00200 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00187
1000 Genomes Project 0.00200
Trans-Omics for Precision Medicine (TOPMed) 0.00276
Exome Aggregation Consortium (ExAC) 0.00349
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00362
The Genome Aggregation Database (gnomAD) 0.00375
The Genome Aggregation Database (gnomAD), exomes 0.00383
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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TYR | - | - |
GRCh38 GRCh37 |
657 | 678 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2022 | RCV000003976.17 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV000085913.35 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 14, 2023 | RCV000400442.14 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV000500113.20 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2014 | RCV000623187.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762872.4 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jan 26, 2024 | RCV001375218.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001813946.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2023 | RCV003460414.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV004532283.1 |
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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Likely pathogenic
(May 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Albinism, oculocutaneous, type IA
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597799.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
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Likely pathogenic
(Aug 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Oculocutaneous albinism type 1B
Affected status: no
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845358.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
|
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Pathogenic
(Apr 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700794.2
First in ClinVar: Aug 28, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
|
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Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
None
Tyrosinase-negative oculocutaneous albinism SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Oculocutaneous albinism type 1B
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893252.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(Feb 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Tyrosinase-negative oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000897703.1
First in ClinVar: Apr 25, 2019 Last updated: Apr 25, 2019 |
Comment:
The observed variant NM_000372.4 :c.1217C>T (p.Pro406Leu) is a missense variation found in exon 4 of the TYR gene. It is a known pathogenic variant and … (more)
The observed variant NM_000372.4 :c.1217C>T (p.Pro406Leu) is a missense variation found in exon 4 of the TYR gene. It is a known pathogenic variant and has been reported in the ExAC and gnomAD database with an allele frequency of 0.003489 and 0.003845, respectively. The in silico prediction of this variant is disease causing by MutationTaster2. The proband's parents are heterozygous carriers of the following mutations in the TYR gene: c.1147G>A (p.Asp383Asn) in exon 3 and c.1217C>T (p.pro406leu) in exon 4. As the parents are phenotypically normal, it is likely that these mutations are in a cis arrangement. The proband thus has both of the parent's mutations in trans with a third variant c.1110G>A, which is de novo. In summary, the variant meets the ACMG criteria to be classified as pathogenic based upon the evidence stated above. (less)
Clinical Features:
Ocular albinism (present) , Ocular albinism (present) , Albinism (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Indian Hindu
Geographic origin: India
Method: DNA was used to perform PCR bi-directional Sanger sequencing. Sequence obtained was aligned to a reference gene using BLAST tool and then analyzed using Chromas to identify variants in the targeted gene relevant to the clinical indication.
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Pathogenic
(Aug 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000374875.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TYR c.1217C>T (p.Pro406Leu) missense variant has been reported in five studies in which it is found in at least 25 patients with oculocutaneous albinism … (more)
The TYR c.1217C>T (p.Pro406Leu) missense variant has been reported in five studies in which it is found in at least 25 patients with oculocutaneous albinism (OCA) including in 13 patients in a homozygous state, four patients in a compound heterozygous state, two patients in a heterozygous state, and six individuals whose zygosity was not reported (Giebel et al. 1991; Hutton et al. 2008; Gargiulo et al. 2011; Jaworek et al. 2012; Ghodsinejad Kalahroudi et al. 2014). When clinical subtypes were described, the majority of affected individuals were reported to have OCA type 1. The variant was also detected in nine unaffected heterozygous carriers (Giebel LB et al. 1991). Khordadpoor-Deilamani et al. (2016) additionally found one patient with the p.Pro406Leu variant in a heterozygous state who also carried a homozugous frameshift variant in the SLC45A2 gene. The p.Pro406Leu variant was absent from at least 372 control chromosomes but is reported at a frequency of 0.00696 in the European population of the 1000 Genomes Project. Giebel et al. (1991) demonstrated that the tyrosinase activity in HeLa cells transfected with the p.Pro406Leu variant had only 7% of the activity of wild type. Toyofuku et al. (2001) expressed the p.Pro406Leu variant in COS7 cells and demonstrated that the variant protein is mislocalized, is more sensitive to endoglycosidase H digestion, and degrades more rapidly than wild type protein. Based on the collective evidence, the p.Pro406Leu 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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Likely pathogenic
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712802.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at l east 5 homozygous and 7 compound heterozygous individuals with clinical features of … (more)
The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at l east 5 homozygous and 7 compound heterozygous individuals with clinical features of Oculocutaneous albinism type 1 (OCA type 1), and segregated with disease in 3 affected relatives from 1 family (Giebel 1991, Hutton 2008, Council 2009, Wei 2010, Hu 2011, Gargiulo 2011, Kalahroudi 2014, Rooryck 2008, Gronskov 2009, and Jaworek 2011). This variant has been identified in 1% (275/25738) of Finnish chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitut e.org; dbSNP rs104894313, rs62645921). This variant has also been reported in Cl inVar (Variation ID#3777) as pathogenic or likely pathogenic. In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (Tripathi 1992, Spritz 1997, and Toyofuku 2001). It should be noted that so me studies have indicated that the pseudogene harbors this same variant. In summ ary, although additional studies are required to fully establish its significanc e, this variant is likely pathogenic for OCA type 1 in an autosomal recessive ma nner based upon case observations, segregation studies and in vitro data. ACMG/A MP Criteria applied: PM3 (upgraded to strong based on multiple occurences), PP1, PP3, PP5 (Richards 2015). Although the variant has been confirmed to occur in t he functional copy of the gene in this individual, we cannot guarantee that the evidence in the literature was based on observations in the functional gene. Ple ase note that, due to the technical limitations of the next generation sequencin g and Sanger confirmation assays, the TYR pseudogene cannot be reliably avoided. Therefore, before making clinical decisions regarding this variant, further tes ting via targeted assays that guarantee avoidance of TYR pseudogene would be req uired to confirm the presence of this variant. (less)
Number of individuals with the variant: 2
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
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Oculocutaneous albinism type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe
Accession: SCV000998901.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Clinical Features:
Albinism (present)
Sex: female
Geographic origin: Brazil
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Tyrosinase-negative oculocutaneous albinism
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251449.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The TYR (p.Pro406Leu) variant segregated in a family with type IB oculocutaneous albinism (PMID: 1903591).
Number of individuals with the variant: 1
|
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Likely pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Abnormality of the skin
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755539.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
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Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557667.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with oculocutaneous albinism type IA (MIM#203100) and type IB (MIM#606952). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1190 heterozygotes, 7 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or very highly conserved with a moderate amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a hypomorphic allele and has been reported in multiple individuals with oculocutaneous albinism (PMID: 28667292, 31719542). It has also be reported as pathogenic and VUS in ClinVar. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This OCA1B-related variant is biochemically similar to the wild type but with reduced enzyme activity to 35% (PMID: 27775880). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.1237delG; p.Glu413Lysfs*72) in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579802.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM1, PM3, PS3_SUP, PP1, PP3
|
Number of individuals with the variant: 3
Sex: female
|
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Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844690.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: TYR c.1217C>T (p.Pro406Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: TYR c.1217C>T (p.Pro406Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 250392 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.0038 vs 0.0056), allowing no conclusion about variant significance. c.1217C>T has been reported in the literature in individuals affected with Oculocutaneous Albinism. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in less catalytic activity than the wild-type. Twenty-one clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/likely pathogenic n=18, benign n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021581.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001583161.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 406 of the TYR protein (p.Pro406Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 406 of the TYR protein (p.Pro406Leu). This variant is present in population databases (rs104894313, gnomAD 1.1%), 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: 1903591, 22734612, 25216246, 27734839). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3777). 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 TYR protein function. Experimental studies have shown that this missense change affects TYR function (PMID: 1429711, 9242509, 11284711). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
|
TYR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004730906.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TYR c.1217C>T variant is predicted to result in the amino acid substitution p.Pro406Leu. This variant has been reported in both the homozygous and compound … (more)
The TYR c.1217C>T variant is predicted to result in the amino acid substitution p.Pro406Leu. This variant has been reported in both the homozygous and compound heterozygous states in multiple individuals with oculocutaneous albinism (Giebel et al. 1991. PubMed ID: 1903591; King et al. 2003. PubMed ID: 13680365; Hutton & Spritz. 2008. PubMed ID: 18463683). Functional studies using protein expression in cell culture have shown that the p.Pro406Leu variant results in reduced tyrosinase activity compared to wild-type (Giebel et al. 1991. PubMed ID: 1903591; Dolinska et al. 2017. PubMed ID: 27775880). This variant is reported in 1.1% of alleles in individuals of European (Finnish) descent in gnomAD and with a global allele frequency of 0.39%, including multiple homozygous individuals, indicating this variant is relatively common. Given all the evidence, we interpret c.1217C>T (p.Pro406Leu) as pathogenic. (less)
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Pathogenic
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248577.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
TYR: PM3:Very Strong, PM1, PM2, PM5, PS3:Moderate
Number of individuals with the variant: 16
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138405.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
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Likely pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368755.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PP2,PP3. This variant was detected in homozygous state.
|
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Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001821911.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
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Pathogenic
(Aug 29, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741318.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Albinism (present) , Horizontal nystagmus (present) , Blue irides (present) , White hair (present) , Celiac disease (present) , Dysuria (present) , Abdominal pain (present) … (more)
Albinism (present) , Horizontal nystagmus (present) , Blue irides (present) , White hair (present) , Celiac disease (present) , Dysuria (present) , Abdominal pain (present) , Constipation (present) , Epistaxis (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003841208.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
|
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Likely pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207535.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807577.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
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Albinism, oculocutaneous, type IA
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142424.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000372.4:c.1217C>T in the TYR gene has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in … (more)
NM_000372.4:c.1217C>T in the TYR gene has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The p.Pro406Leu (NM_000372.4 c.1217C>T) variant in TYR has been reported in at least 5 homozygous and 7 compound heterozygous individuals with clinical features of Oculocutaneous albinism type 1 (OCA type 1) (PMID: 18463683; 19320745; 19865097; 20861488; 25216246). In vitro function al studies provide evidence that the p.Pro406Leu variant may impact protein func tion (PMID: 1642278; 9242509; 11284711).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; 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
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549874.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TYR p.P406L variant was identified in 20 of 528 proband chromosomes (frequency: 0.038; 5 homozygotes, 6 compound heterozygotes, 4 heterozygotes) from individuals or families … (more)
The TYR p.P406L variant was identified in 20 of 528 proband chromosomes (frequency: 0.038; 5 homozygotes, 6 compound heterozygotes, 4 heterozygotes) from individuals or families with Oculocutaneous Albinism (Giebel_1991_PMID:1903591; Hutton_2008_PMID:18463683; Khordadpoor-Deilamani_2016_PMID:26167114; Kalahroudi_2014_PMID:25216246; Norman_2017_PMID:28667292; Gao_2017_PMID:28451379). This variant was also identified as a heterozygous variant in patient with basal cell carcinoma from a cohort of 287 patients with a suspected predisposition of skin cancer (Hu_2011_PMID:21906913), and as a homozygous variant in one of 138 patients with primary cutaneous melanoma (Council_2009_PMID:19320745). The variant was identified in dbSNP (ID: rs104894313) and ClinVar (classified as pathogenic by Ambry Genetics, EGl Genetics and three other laboratories, and as likely pathogenic by Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and two other laboratories). The variant was identified in control databases in 1104 of 281766 chromosomes (7 homozygous) at a frequency of 0.003918 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 273 of 25062 chromosomes (freq: 0.01089), Ashkenazi Jewish in 87 of 10350 chromosomes (freq: 0.008406), Other in 35 of 7178 chromosomes (freq: 0.004876), European (non-Finnish) in 555 of 128466 chromosomes (freq: 0.00432), Latino in 69 of 35262 chromosomes (freq: 0.001957), South Asian in 57 of 30608 chromosomes (freq: 0.001862), African in 26 of 24912 chromosomes (freq: 0.001044), and East Asian in 2 of 19928 chromosomes (freq: 0.0001). The p.Pro406 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies demonstrated that the p.P406L variant destabilizes tyrosinase structure and results in reduced protein activity compared to wildtype (Giebel_1991_PMID_1903591; Dolinksa_2017_PMID_27775880; Toyofuku_2001_PMID_11284711; Spritz_1997_PMID_9242509). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Jul 15, 1992)
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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: SCV000024141.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
In an Amish kindred with oculocutaneous albinism (OCA1B; 606952) reported by Nance et al. (1970), Giebel et al. (1990) observed a substitution of leucine for … (more)
In an Amish kindred with oculocutaneous albinism (OCA1B; 606952) reported by Nance et al. (1970), Giebel et al. (1990) observed a substitution of leucine for proline at position 406 of the tyrosinase gene. Tripathi et al. (1992) stated that this mutation had been found only among the Amish. (less)
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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:
unknown
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Retina International
Accession: SCV000118056.1
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.1217C>T
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Uncertain significance
(Apr 11, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Oculocutaneous albinism type 1B
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001524702.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported as disease-causing [PMID 1642278, … (more)
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported as disease-causing [PMID 1642278, 28266639, 1903591, 27775880, 25333069, 21906913, 28667292, 24123366, 9242509, 11284711, 1429711] (less)
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Uncertain significance
(Apr 12, 2021)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571920.2
First in ClinVar: May 01, 2021 Last updated: Aug 21, 2021 |
Comment:
PM5_Strong, PP3_Supporting
Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
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Benign
(May 06, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002499801.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Functional studies suggest a damaging effect with temperature-sensitive tyrosine hydroxylase activity and abnormal subcellular trafficking compared to wild type (Tripathi et al., 1992; Toyofuku et … (more)
Functional studies suggest a damaging effect with temperature-sensitive tyrosine hydroxylase activity and abnormal subcellular trafficking compared to wild type (Tripathi et al., 1992; Toyofuku et al., 2001; Dolinska et al., 2017); This variant is associated with the following publications: (PMID: 27775880, 21541274, 11284711, 24123366, 1429711, 21906913, 9242509, 25333069, 30609409, 28667292, 13680365, 15146472, 18463683, 25216246, 22734612, 20861488, 27887888, 1903591, 31382929, 31322791, 28976636, 31980526, 34426522, 31589614, 31719542) (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000897703.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Non-syndromic Oculocutaneous Albinism: Novel Genetic Variants and Clinical Follow Up of a Brazilian Pediatric Cohort. | Schidlowski L | Frontiers in genetics | 2020 | PMID: 32411182 |
Clinical and genetic variability in children with partial albinism. | Campbell P | Scientific reports | 2019 | PMID: 31719542 |
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 outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. | Shahzad M | Scientific reports | 2017 | PMID: 28266639 |
Evaluating outer segment length as a surrogate measure of peak foveal cone density. | Wilk MA | Vision research | 2017 | PMID: 27887888 |
Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. | Dolinska MB | Pigment cell & melanoma research | 2017 | PMID: 27775880 |
Clinical evaluation and molecular screening of a large consecutive series of albino patients. | Mauri L | Journal of human genetics | 2017 | PMID: 27734839 |
Homozygosity mapping in albinism patients using a novel panel of 13 STR markers inside the nonsyndromic OCA genes: introducing 5 novel mutations. | Khordadpoor-Deilamani F | Journal of human genetics | 2016 | PMID: 26818737 |
Sequence analysis of tyrosinase gene in ocular and oculocutaneous albinism patients: introducing three novel mutations. | Khordadpoor-Deilamani F | Molecular vision | 2015 | PMID: 26167114 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1). | Ghodsinejad Kalahroudi V | PloS one | 2014 | PMID: 25216246 |
Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. | Rodriguez-Flores JL | Human mutation | 2014 | PMID: 24123366 |
Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population. | Jaworek TJ | Orphanet journal of rare diseases | 2012 | PMID: 22734612 |
Assessment of tyrosinase variants and skin cancer risk in a large cohort of French subjects. | Hu HH | Journal of dermatological science | 2011 | PMID: 21906913 |
Molecular and clinical characterization of albinism in a large cohort of Italian patients. | Gargiulo A | Investigative ophthalmology & visual science | 2011 | PMID: 20861488 |
A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism. | Wei A | The Journal of investigative dermatology | 2010 | PMID: 19865097 |
Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients. | Council ML | Experimental dermatology | 2009 | PMID: 19320745 |
The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. | Oetting WS | American journal of medical genetics. Part A | 2009 | PMID: 19208379 |
Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism. | Grønskov K | Investigative ophthalmology & visual science | 2009 | PMID: 19060277 |
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 |
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 |
The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. | Toyofuku K | The Biochemical journal | 2001 | PMID: 11284711 |
Mutational analysis of copper binding by human tyrosinase. | Spritz RA | The Journal of investigative dermatology | 1997 | PMID: 9242509 |
Tyrosinase gene mutations in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions. | Tripathi RK | American journal of medical genetics | 1992 | PMID: 1642278 |
Mutational mapping of the catalytic activities of human tyrosinase. | Tripathi RK | The Journal of biological chemistry | 1992 | PMID: 1429711 |
Tyrosinase gene mutations associated with type IB ("yellow") oculocutaneous albinism. | Giebel LB | American journal of human genetics | 1991 | PMID: 1903591 |
Amish albinism: a distinctive autosomal recessive phenotype. | Nance WE | American journal of human genetics | 1970 | PMID: 5516239 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
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Text-mined citations for rs104894313 ...
HelpRecord last updated May 12, 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.