VCV000003793.37 - ClinVar

NM_000372.5(TYR):c.61C>T (p.Pro21Ser)

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.

(9)

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.61C>T (p.Pro21Ser)

Variation ID: 3793 Accession: VCV000003793.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q14.3 11: 89178014 (GRCh38) [ NCBI UCSC ] 11: 88911182 (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	Jan 25, 2025	Apr 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000372.5:c.61C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000363.1:p.Pro21Ser	missense
NC_000011.10:g.89178014C>T
NC_000011.9:g.88911182C>T
NG_008748.1:g.5143C>T
	P14679:p.Pro21Ser

... more HGVS ... less HGVS

Protein change

P21S

Other names

Canonical SPDI

NC_000011.10:89178013:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA227575 UniProtKB: P14679#VAR_007650 OMIM: 606933.0023 dbSNP: rs61753178 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	710	732

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.
Tyrosinase-negative oculocutaneous albinism	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000003996.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 9, 2023	RCV000085959.29
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	Pathogenic (1)	criteria provided, single submitter	Mar 17, 2024	RCV004566679.1
Oculocutaneous albinism type 1B SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Tyrosinase-negative oculocutaneous albinism	Pathogenic (1)	criteria provided, single submitter	Apr 3, 2024	RCV005003328.1
Oculocutaneous albinism type 1B	Pathogenic (1)	criteria provided, single submitter	Feb 19, 2024	RCV004783717.1

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 (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tyrosinase-negative oculocutaneous albinism Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001821915.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tyrosinase-negative oculocutaneous albinism Affected status: yes Allele origin: germline	3billion Accession: SCV002572799.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (2) PubMed: 22734612‚ 1642278 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Missense changes are a common disease-causing mechanism. … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.53). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003793). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1642278). A different missense change at the same codon (p.Pro21Leu) has been reported to be associated with TYR -related disorder (PMID: 22734612). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Albinism (present) , Ocular albinism (present) , Horizontal nystagmus (present) , Exophoria (present) , Foveal hypoplasia (present) , Astigmatism (present) , Hypermetropia (present) , Amblyopia … (more) Albinism (present) , Ocular albinism (present) , Horizontal nystagmus (present) , Exophoria (present) , Foveal hypoplasia (present) , Astigmatism (present) , Hypermetropia (present) , Amblyopia (present) , Joint laxity (present) (less) Zygosity: Single Heterozygote
Pathogenic (Dec 09, 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: SCV003440454.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 1642278‚ 13680365‚ 19060277‚ 20861488 Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the TYR protein (p.Pro21Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the TYR protein (p.Pro21Ser). This variant is present in population databases (rs61753178, gnomAD 0.008%). This missense change has been observed in individuals with ocular albinism (PMID: 1642278, 13680365, 19060277, 20861488). ClinVar contains an entry for this variant (Variation ID: 3793). 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)
Pathogenic (Feb 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Oculocutaneous albinism type 1B (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397662.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (6) PubMed: 1642278‚ 26167114‚ 13680365‚ 30472657‚ 27734839‚ 19060277 Comment: This sequence variant is a single nucleotide substitution (C>T) at position 61 of the coding sequence of the TYR gene that results in a proline … (more) This sequence variant is a single nucleotide substitution (C>T) at position 61 of the coding sequence of the TYR gene that results in a proline to serine amino acid change at residue 21 of the tyrosinase protein. This is a previously reported variant (ClinVar 3793) that has been observed in numerous homozygous and compound heterozygous individuals affected by oculocutaneous albinism (PMID: 1642278, 13680365, 19060277, 26167114, 27734839, 30472657). This variant is present in 11 of 403646 alleles (0.0027%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Pro21 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM3, PP2, PP3, PS4 (less)
Pathogenic (Apr 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tyrosinase-negative oculocutaneous albinism SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Oculocutaneous albinism type 1B Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005631902.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Mar 17, 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: SCV005054562.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247945.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 3
Pathogenic (Jul 15, 1992)	no assertion criteria provided Method: literature only	ALBINISM, OCULOCUTANEOUS, TYPE IA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024162.2 First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020	Publications: PubMed (1) PubMed: 1642278 Comment on evidence: In a Caucasian girl with type IA OCA (OCA1A; 203100) Tripathi et al. (1992) identified a CCT(pro)-to-TCT(ser) mutation at codon 21 of the TYR gene, … (more) In a Caucasian girl with type IA OCA (OCA1A; 203100) Tripathi et al. (1992) identified a CCT(pro)-to-TCT(ser) mutation at codon 21 of the TYR gene, resulting in a pro21-to-ser (P21S) substitution. The P21S mutation was found in compound heterozygosity with a 1-bp deletion (CTT to CT) (606933.0029) in codon 388, which created a frameshift. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000118102.1 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.61C>T

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.53). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003793). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1642278). A different missense change at the same codon (p.Pro21Leu) has been reported to be associated with TYR -related disorder (PMID: 22734612). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the TYR protein (p.Pro21Ser). This variant is present in population databases (rs61753178, gnomAD 0.008%). This missense change has been observed in individuals with ocular albinism (PMID: 1642278, 13680365, 19060277, 20861488). ClinVar contains an entry for this variant (Variation ID: 3793). 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.

Comment:

This sequence variant is a single nucleotide substitution (C>T) at position 61 of the coding sequence of the TYR gene that results in a proline to serine amino acid change at residue 21 of the tyrosinase protein. This is a previously reported variant (ClinVar 3793) that has been observed in numerous homozygous and compound heterozygous individuals affected by oculocutaneous albinism (PMID: 1642278, 13680365, 19060277, 26167114, 27734839, 30472657). This variant is present in 11 of 403646 alleles (0.0027%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Pro21 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM3, PP2, PP3, PS4

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
Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene.	Monfermé S	The British journal of ophthalmology	2019	PMID: 30472657
Clinical evaluation and molecular screening of a large consecutive series of albino patients.	Mauri L	Journal of human genetics	2017	PMID: 27734839
Sequence analysis of tyrosinase gene in ocular and oculocutaneous albinism patients: introducing three novel mutations.	Khordadpoor-Deilamani F	Molecular vision	2015	PMID: 26167114
Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population.	Jaworek TJ	Orphanet journal of rare diseases	2012	PMID: 22734612
Molecular and clinical characterization of albinism in a large cohort of Italian patients.	Gargiulo A	Investigative ophthalmology & visual science	2011	PMID: 20861488
Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism.	Grønskov K	Investigative ophthalmology & visual science	2009	PMID: 19060277
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

Text-mined citations for rs61753178 ...

These 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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000372.5(TYR):c.61C>T (p.Pro21Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61753178 ...