VCV002632089.3 - ClinVar

NM_000372.5(TYR):c.573del (p.Ser192fs)

Germline

Classification

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.

(3)

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

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.573del (p.Ser192fs)

Variation ID: 2632089 Accession: VCV002632089.3

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11q14.3 11: 89178526 (GRCh38) [ NCBI UCSC ] 11: 88911694 (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	Nov 20, 2023	Jun 17, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000372.5:c.573del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000363.1:p.Ser192fs	frameshift
NC_000011.10:g.89178526del
NC_000011.9:g.88911694del
NG_008748.1:g.5655del

Protein change

S192fs

Other names

Canonical SPDI

NC_000011.10:89178525:A:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	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	683	704

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 21, 2023	RCV003553902.2
TYR-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 2, 2023	RCV004528594.1
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	Pathogenic (1)	criteria provided, single submitter	Mar 26, 2024	RCV004572970.1

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 (Oct 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TYR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107093.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The TYR c.573delA variant is predicted to result in a frameshift and premature protein termination (p.Ser192Leufs34). This variant was reported in the homozygous and compound … (more) The TYR c.573delA variant is predicted to result in a frameshift and premature protein termination (p.Ser192Leufs34). This variant was reported in the homozygous and compound heterozygous states in two individuals with oculocutaneous albinism (King et al. 2003. PubMed ID: 13680365). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88911693-GA-G). Frameshift variants in TYR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004296103.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 23504663‚ 13680365 Comment: This sequence change creates a premature translational stop signal (p.Ser192Leufs34) 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.Ser192Leufs34) 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 (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 13680365). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054558.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

The TYR c.573delA variant is predicted to result in a frameshift and premature protein termination (p.Ser192Leufs*34). This variant was reported in the homozygous and compound heterozygous states in two individuals with oculocutaneous albinism (King et al. 2003. PubMed ID: 13680365). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88911693-GA-G). Frameshift variants in TYR are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser192Leufs*34) 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 (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 13680365). For these reasons, this variant has been classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics.	Simeonov DR	Human mutation	2013	PMID: 23504663
Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype.	King RA	Human genetics	2003	PMID: 13680365

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000372.5(TYR):c.573del (p.Ser192fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...