ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.1336G>A (p.Gly446Ser)
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.1336G>A (p.Gly446Ser)
Variation ID: 3801 Accession: VCV000003801.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.3 11: 89284924 (GRCh38) [ NCBI UCSC ] 11: 89018092 (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 Apr 15, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000372.5:c.1336G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000363.1:p.Gly446Ser missense NC_000011.10:g.89284924G>A NC_000011.9:g.89018092G>A NG_008748.1:g.112053G>A P14679:p.Gly446Ser - Protein change
- G446S
- Other names
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- Canonical SPDI
- NC_000011.10:89284923: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
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
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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
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TYR | - | - |
GRCh38 GRCh37 |
649 | 670 |
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 (2) |
criteria provided, single submitter
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Jul 22, 2021 | RCV000004005.9 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000085920.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2016 | RCV000602413.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2021 | RCV002496250.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV003944799.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 23, 2023 | RCV003325937.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2023 | RCV003466803.1 |
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
(Nov 15, 2016)
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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: SCV000731266.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly446Ser variant in TYR has been reported in at least 9 compound heterozy gous individuals with oculocutaneous albinism type 1 (King 2003, Hutton 2008). … (more)
The p.Gly446Ser variant in TYR has been reported in at least 9 compound heterozy gous individuals with oculocutaneous albinism type 1 (King 2003, Hutton 2008). T his variant has been identified in 3/66378 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894317) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency. In summary, th is variant meets criteria to be classified as pathogenic for oculocutaneous albi nism type 1 in an autosomal recessive manner based upon its occurrence in affect ed individuals and low frequency in control populations. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 06, 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: SCV002814206.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 15, 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: SCV000779693.5
First in ClinVar: Feb 20, 2014 Last updated: Aug 31, 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: 30609409, … (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: 30609409, 28976636, 10987646, 1642278, 9259202, 13680365, 29345414, 31589614, 31980526, 21906913, 33808351, 18463683) (less)
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Pathogenic
(Oct 20, 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: SCV004207548.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 19, 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: SCV001589665.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 446 of the TYR protein (p.Gly446Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 446 of the TYR protein (p.Gly446Ser). This variant is present in population databases (rs104894317, gnomAD 0.01%). This missense change has been observed in individual(s) with albinism (PMID: 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3801). 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
(Jan 03, 2024)
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criteria provided, single submitter
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: SCV004760635.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TYR c.1336G>A variant is predicted to result in the amino acid substitution p.Gly446Ser. This variant has been reported many times along with a second … (more)
The TYR c.1336G>A variant is predicted to result in the amino acid substitution p.Gly446Ser. This variant has been reported many times along with a second pathogenic variant in TYR in individuals with oculocutaneous albinism (see for examples Tripathi et al. 1992. PubMed ID: 1642278; King et al. 2003. PubMed ID: 13680365; Marti et al. 2018. PubMed ID: 28976636). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3801). Given the evidence, we interpret c.1336G>A (p.Gly446Ser) as pathogenic. (less)
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Pathogenic
(Dec 09, 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: SCV000338204.4
First in ClinVar: Dec 06, 2016 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: SCV001821972.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Oculocutaneous albinism type 1B
Affected status: yes
Allele origin:
germline
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Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853414.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
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Pathogenic
(May 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010111.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
TYR: PM3:Strong, PM1, PM2:Supporting, PP3, PP4, PS4:Supporting
Number of individuals with the variant: 1
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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 IA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024171.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
See Tripathi et al. (1992) for the GGC(gly)-to-AGC(ser) mutation in codon 446.
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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: SCV000118063.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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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 |
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 |
Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. | King RA | Human genetics | 2003 | PMID: 13680365 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
Text-mined citations for rs104894317 ...
HelpRecord last updated Apr 15, 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.