ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.140G>A (p.Gly47Asp)
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.140G>A (p.Gly47Asp)
Variation ID: 3794 Accession: VCV000003794.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.3 11: 89178093 (GRCh38) [ NCBI UCSC ] 11: 88911261 (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 4, 2013 Oct 8, 2024 Mar 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000372.5:c.140G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000363.1:p.Gly47Asp missense NC_000011.10:g.89178093G>A NC_000011.9:g.88911261G>A NG_008748.1:g.5222G>A P14679:p.Gly47Asp - Protein change
- G47D
- Other names
- -
- Canonical SPDI
- NC_000011.10:89178092:G:A
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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 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00016
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00048
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
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 |
681 | 702 |
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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Jul 22, 2021 | RCV000003997.11 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 15, 2008 | RCV000003998.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2024 | RCV000085925.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763287.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2018 | RCV001267064.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2024 | RCV003460421.3 | |
TYR-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jul 26, 2024 | RCV004532284.2 |
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
(Dec 14, 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: SCV000597781.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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None
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: SCV000893934.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV001821919.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Jan 10, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002229417.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 47 of the TYR protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 47 of the TYR protein (p.Gly47Asp). This variant is present in population databases (rs61753180, gnomAD 0.1%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1676041, 8128955, 8434585, 16417222, 19626598, 23242301, 23882993, 28976636). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Puerto Rican or Moroccan Jewish ancestry (PMID: 8128955, 8434585, 16417222, 23882993). ClinVar contains an entry for this variant (Variation ID: 3794). 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%. This variant disrupts the p.Gly47 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 8434585, 26167114, 29345414), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 09, 2024)
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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: SCV000515217.7
First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024 |
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: 18925668, … (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: 18925668, 1642278, 28976636, 31589614, 33599182, 29345414, 8434585) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Tyrosinase-negative oculocutaneous albinism
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe
Accession: SCV000998906.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Clinical Features:
Albinism (present)
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Brazil
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Pathogenic
(Feb 26, 2018)
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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: SCV001445245.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Congenital total pulmonary venous return anomaly (present) , Global developmental delay (present) , Muscular hypotonia (present) , Microcephaly (present) , Premature birth (present) , Severe … (more)
Congenital total pulmonary venous return anomaly (present) , Global developmental delay (present) , Muscular hypotonia (present) , Microcephaly (present) , Premature birth (present) , Severe Myopia (present) , Nystagmus (present) , Astigmatism (present) , Albinism (present) (less)
Sex: female
Ethnicity/Population group: Mexican
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Pathogenic
(Mar 20, 2024)
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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: SCV004207551.3
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Nov 15, 2008)
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no assertion criteria provided
Method: literature only
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ALBINISM, OCULOCUTANEOUS, TYPE IA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024163.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020 |
Comment on evidence:
See Tripathi et al. (1992) for the GGC(gly)-to-GAC(asp) mutation at codon 47. Oetting et al. (1993) found this mutation to be frequent among albinos in … (more)
See Tripathi et al. (1992) for the GGC(gly)-to-GAC(asp) mutation at codon 47. Oetting et al. (1993) found this mutation to be frequent among albinos in Puerto Rico. They found the G47D mutation in homozygous state in 9 of 12 unrelated Puerto Ricans with type IA oculocutaneous albinism (OCA1A; 203100). Two other individuals were heterozygous for the mutation; 1 of these had the T373K mutation (606933.0003) in the homologous allele. One of the individuals with Negroid features was homozygous for a W236X mutation (606933.0035). Because of the migration between Puerto Rico and the Canary Islands, 3 persons with OCA from the Canary Islands were analyzed. One was a genetic compound for the G47D mutation and a novel L216M mutation (606933.0036), one was homozygous for the P81L mutation (606933.0002), and one was heterozygous for the P81L mutation. Haplotype analysis in the Puerto Rican cases showed that the G47D mutation occurred on a single haplotype, consistent with a common ancestor for all individuals having this mutation. Two different haplotypes were found associated with the P81L mutation, suggesting that this may be either a recurring mutation for the tyrosinase gene or a recombination between haplotypes. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B (606952). A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D and the hypomorphic allele R402Q (606933.0009). Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. (less)
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Pathogenic
(Nov 15, 2008)
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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: SCV000024164.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020 |
Comment on evidence:
See Tripathi et al. (1992) for the GGC(gly)-to-GAC(asp) mutation at codon 47. Oetting et al. (1993) found this mutation to be frequent among albinos in … (more)
See Tripathi et al. (1992) for the GGC(gly)-to-GAC(asp) mutation at codon 47. Oetting et al. (1993) found this mutation to be frequent among albinos in Puerto Rico. They found the G47D mutation in homozygous state in 9 of 12 unrelated Puerto Ricans with type IA oculocutaneous albinism (OCA1A; 203100). Two other individuals were heterozygous for the mutation; 1 of these had the T373K mutation (606933.0003) in the homologous allele. One of the individuals with Negroid features was homozygous for a W236X mutation (606933.0035). Because of the migration between Puerto Rico and the Canary Islands, 3 persons with OCA from the Canary Islands were analyzed. One was a genetic compound for the G47D mutation and a novel L216M mutation (606933.0036), one was homozygous for the P81L mutation (606933.0002), and one was heterozygous for the P81L mutation. Haplotype analysis in the Puerto Rican cases showed that the G47D mutation occurred on a single haplotype, consistent with a common ancestor for all individuals having this mutation. Two different haplotypes were found associated with the P81L mutation, suggesting that this may be either a recurring mutation for the tyrosinase gene or a recombination between haplotypes. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B (606952). A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D and the hypomorphic allele R402Q (606933.0009). Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. (less)
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Pathogenic
(Jul 26, 2024)
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no assertion criteria provided
Method: clinical testing
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TYR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114982.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The TYR c.140G>A variant is predicted to result in the amino acid substitution p.Gly47Asp. This variant has been reported many times as causative for autosomal … (more)
The TYR c.140G>A variant is predicted to result in the amino acid substitution p.Gly47Asp. This variant has been reported many times as causative for autosomal recessive oculocutaneous albinism (see for examples Oetting et al. 1993. PubMed ID: 8434585; Gershoni-Baruch et al. 1994. PubMed ID: 8128955; Camand et al. 2001. PubMed ID: 11295837; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3794). Given all the evidence, we interpret this variant as pathogenic. (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: SCV000118068.1
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.140G>A
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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 |
Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting. | Marti A | Pigment cell & melanoma research | 2018 | PMID: 28976636 |
Sequence analysis of tyrosinase gene in ocular and oculocutaneous albinism patients: introducing three novel mutations. | Khordadpoor-Deilamani F | Molecular vision | 2015 | PMID: 26167114 |
Ocular findings in patients with oculocutaneous albinism type ia with G47D tyrosinase gene mutation in Puerto Rico: a case report. | Rodríguez-Agramonte F | Boletin de la Asociacion Medica de Puerto Rico | 2013 | PMID: 23882993 |
[An overview of oculocutaneous albinism: TYR gene mutations in five Colombian individuals]. | Sanabria D | Biomedica : revista del Instituto Nacional de Salud | 2012 | PMID: 23242301 |
Prenatal molecular diagnosis of oculocutaneous albinism (OCA) in a large cohort of Israeli families. | Rosenmann A | Prenatal diagnosis | 2009 | PMID: 19626598 |
A new hypothesis of OCA1B. | Chiang PW | American journal of medical genetics. Part A | 2008 | PMID: 18925668 |
Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico. | Santiago Borrero PJ | The Journal of investigative dermatology | 2006 | PMID: 16417222 |
Mutations of the tyrosinase gene in patients with oculocutaneous albinism from various ethnic groups in Israel. | Gershoni-Baruch R | American journal of human genetics | 1994 | PMID: 8128955 |
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 in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions. | Tripathi RK | American journal of medical genetics | 1992 | PMID: 1642278 |
Molecular analysis of an extended family with type IA (tyrosinase-negative) oculocutaneous albinism. | Oetting WS | The Journal of investigative dermatology | 1991 | PMID: 1676041 |
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Text-mined citations for rs61753180 ...
HelpRecord last updated Oct 13, 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.