This sequence change creates a premature translational stop signal (p.Cys244*) in the TYR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663). This variant is present in population databases (rs747193559, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 28667292, 28771251, 28976636). 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: 3787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000372.5(TYR):c.732_733del (p.Cys244_Asp245delinsTer)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000372.5(TYR):c.732_733del (p.Cys244_Asp245delinsTer)
Variation ID: 3787 Accession: VCV000003787.46
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 11q14.3 11: 89178682-89178683 (GRCh38) [ NCBI UCSC ] 11: 88911850-88911851 (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 20, 2024 May 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000372.5:c.732_733del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000363.1:p.Cys244_Asp245delinsTer nonsense NM_000372.4:c.730_731delTG NM_000372.4:c.732_733del NC_000011.10:g.89178683TG[1] NC_000011.9:g.88911851TG[1] NG_008748.1:g.5812TG[1] NG_008748.1:g.5814_5815del - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000011.10:89178681:GTGTG:GTG
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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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TYR | - | - |
GRCh38 GRCh37 |
689 | 710 | |
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 (2) |
criteria provided, single submitter
|
Jul 22, 2021 | RCV000003990.16 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
May 9, 2024 | RCV000085968.43 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 14, 2024 | RCV003460417.2 | |
|
TYR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2024 | RCV004739288.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002235136.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys244*) in the TYR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys244*) in the TYR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663). This variant is present in population databases (rs747193559, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 28667292, 28771251, 28976636). 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: 3787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207607.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617795.5
First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28771251, 28667292, 28976636, 28451379, 23504663, 1905879) (less)
|
|
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Pathogenic
(Mar 12, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224202.5
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)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinase-negative oculocutaneous albinism
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001821941.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
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Pathogenic
(Apr 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022495.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jul 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248570.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jul 01, 1991)
|
no assertion criteria provided
Method: literature only
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ALBINISM, OCULOCUTANEOUS, TYPE IA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024156.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 09, 2020 |
Comment on evidence:
In a case of type IA oculocutaneous albinism (OCA1A; 203100), Oetting et al. (1991) found deletion of a TG dinucleotide from codons 244 and 245 … (more)
In a case of type IA oculocutaneous albinism (OCA1A; 203100), Oetting et al. (1991) found deletion of a TG dinucleotide from codons 244 and 245 converting TGTGAC to TGAC and leading to premature termination at the TGA signal. (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TYR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005350310.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TYR c.732_733delTG variant is predicted to result in premature protein termination (p.Cys244*). This variant has been reported in the compound heterozygous state in multiple … (more)
The TYR c.732_733delTG variant is predicted to result in premature protein termination (p.Cys244*). This variant has been reported in the compound heterozygous state in multiple individuals with oculocutaneous albinism (Oetting et al. 1991. PubMed ID: 1905879; Norman et al. 2017. PubMed ID: 28667292; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TYR are an established mechanism of disease. Given all the evidence, we interpret this variant as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Retina International
Accession: SCV000118111.1
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.730_731delTG
|
|
Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28771251, 28667292, 28976636, 28451379, 23504663, 1905879)
Comment:
The TYR c.732_733delTG variant is predicted to result in premature protein termination (p.Cys244*). This variant has been reported in the compound heterozygous state in multiple individuals with oculocutaneous albinism (Oetting et al. 1991. PubMed ID: 1905879; Norman et al. 2017. PubMed ID: 28667292; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TYR are an established mechanism of disease. Given all the evidence, we interpret this variant as pathogenic.
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. |
Comment:
This sequence change creates a premature translational stop signal (p.Cys244*) in the TYR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663). This variant is present in population databases (rs747193559, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 28667292, 28771251, 28976636). 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: 3787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28771251, 28667292, 28976636, 28451379, 23504663, 1905879)
Comment:
The TYR c.732_733delTG variant is predicted to result in premature protein termination (p.Cys244*). This variant has been reported in the compound heterozygous state in multiple individuals with oculocutaneous albinism (Oetting et al. 1991. PubMed ID: 1905879; Norman et al. 2017. PubMed ID: 28667292; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TYR are an established mechanism of disease. Given all the evidence, we interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting. | Marti A | Pigment cell & melanoma research | 2018 | PMID: 28976636 |
| Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. | Lionel AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28771251 |
| 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 |
| DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. | Simeonov DR | Human mutation | 2013 | PMID: 23504663 |
| Three different frameshift mutations of the tyrosinase gene in type IA oculocutaneous albinism. | Oetting WS | American journal of human genetics | 1991 | PMID: 1905879 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR | - | - | - | - |
Text-mined citations for rs61754368 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 30, 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.