VCV000003796.23 - ClinVar

NM_000372.5(TYR):c.896G>A (p.Arg299His)

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.

(14)

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.896G>A (p.Arg299His)

Variation ID: 3796 Accession: VCV000003796.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q14.3 11: 89191278 (GRCh38) [ NCBI UCSC ] 11: 88924446 (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	Nov 30, 2024	Mar 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000372.5:c.896G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000363.1:p.Arg299His	missense
NC_000011.10:g.89191278G>A
NC_000011.9:g.88924446G>A
NG_008748.1:g.18407G>A
	P14679:p.Arg299His

... more HGVS ... less HGVS

Protein change

R299H

Other names

Canonical SPDI

NC_000011.10:89191277:G: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.

0.00020 (A)

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

The Genome Aggregation Database (gnomAD) 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00008

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

OMIM: 606933.0026 dbSNP: rs61754375 ClinGen: CA227600 UniProtKB: P14679#VAR_007671 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	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.
Tyrosinase-negative oculocutaneous albinism	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 22, 2021	RCV000004000.12
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV000085979.17
Nonsyndromic Oculocutaneous Albinism	Likely pathogenic (1)	no assertion criteria provided	Mar 7, 2017	RCV000755072.2
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	Pathogenic (1)	criteria provided, single submitter	Mar 28, 2024	RCV003460423.2
Oculocutaneous albinism	Pathogenic (1)	criteria provided, single submitter	Dec 8, 2023	RCV003492282.1
Oculocutaneous albinism type 1B Tyrosinase-negative oculocutaneous albinism	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 31, 2023	RCV003488321.2
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2022	RCV003156055.1

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 25, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003798709.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: Reported as one of the most common pathogenic variants in the TYR gene among individuals of Chinese background (Wei et al., 2010); In silico analysis … (more) Reported as one of the most common pathogenic variants in the TYR gene among individuals of Chinese background (Wei et al., 2010); 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: 26165494, 20447099, 32552135, 1642278, 25919014, 19865097, 28112372, 22294196, 28266639, 30833958, 31199599, 30558096, 31077556, 32966289, 33124154, 31589614) (less)
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Tyrosinase-negative oculocutaneous albinism 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: yes Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: UCC-HudsonAlpha Accession: SCV004232709.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Number of individuals with the variant: 1 Clinical Features: Intellectual disability (present) , Expressive language delay (present) , Receptive language delay (present) , Ocular albinism (present) , Autism (present) , Dystonic disorder (present) , … (more) Intellectual disability (present) , Expressive language delay (present) , Receptive language delay (present) , Ocular albinism (present) , Autism (present) , Dystonic disorder (present) , Tics (present) , Macular hypoplasia (present) (less)
Pathogenic (Jan 11, 2024)	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: SCV002238914.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 1642278‚ 28112372‚ 28266639 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 299 of the TYR protein (p.Arg299His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 299 of the TYR protein (p.Arg299His). This variant is present in population databases (rs61754375, gnomAD 0.03%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1642278, 28112372, 28266639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3796). 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 (Jan 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Albinism, oculocutaneous, type IA Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000597793.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Nov 09, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000336496.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 1642278‚ 19865097‚ 25919014 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TYR Number of individuals with the variant: 1 Sex: mixed
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: SCV001821950.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Pathogenic (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: unknown	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV003845218.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Clinical Features: Abnormality of hair pigmentation (present) , Albinism (present) , Microcytic anemia (present) , Normochromic microcytic anemia (present) , Ocular albinism (present) , Patent foramen ovale … (more) Abnormality of hair pigmentation (present) , Albinism (present) , Microcytic anemia (present) , Normochromic microcytic anemia (present) , Ocular albinism (present) , Patent foramen ovale (present) , Pulmonary arterial hypertension (present) , Recurrent Klebsiella infections (present) , Thrombocytopenia (present) (less)
Pathogenic (Apr 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022494.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 08, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Oculocutaneous albinism Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241997.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (1) PubMed: 24721949 Comment: Variant summary: TYR c.896G>A (p.Arg299His) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Five … (more) Variant summary: TYR c.896G>A (p.Arg299His) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (6.8e-05 vs 0.0056), allowing no conclusion about variant significance. c.896G>A has been reported in the literature in multiple bi-alleleic individuals affected with Oculocutaneous Albinism (example: Lin_2014). Other Variants affecting this residue (p.Arg299Ser, p.Arg299Cys) have been classified pathogenic in ClinVar. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24721949). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 28, 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: SCV004207538.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tyrosinase-negative oculocutaneous albinism 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: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005418444.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PP3+PM3_VeryStrong+PP4+PM5_Strong+PM2_Supporting
Likely pathogenic (Mar 07, 2017)	no assertion criteria provided Method: research	Nonsyndromic Oculocutaneous Albinism Affected status: yes Allele origin: unknown	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000882890.1 First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019	Publications: PubMed (1) PubMed: 28266639
Pathogenic (Jul 15, 1992)	no assertion criteria provided Method: literature only	ALBINISM, OCULOCUTANEOUS, TYPE IA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024166.2 First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020	Publications: PubMed (1) PubMed: 1642278 Comment on evidence: See Tripathi et al. (1992) for the CGT(arg)-to-CAT(his) mutation at codon 299 found in patients with oculocutaneous albinism type 1A (OCA1A; 203100).
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000118122.1 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.896G>A
click to load more click to collapse

Comment:

Reported as one of the most common pathogenic variants in the TYR gene among individuals of Chinese background (Wei et al., 2010); 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: 26165494, 20447099, 32552135, 1642278, 25919014, 19865097, 28112372, 22294196, 28266639, 30833958, 31199599, 30558096, 31077556, 32966289, 33124154, 31589614)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 299 of the TYR protein (p.Arg299His). This variant is present in population databases (rs61754375, gnomAD 0.03%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1642278, 28112372, 28266639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3796). 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:

Variant summary: TYR c.896G>A (p.Arg299His) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (6.8e-05 vs 0.0056), allowing no conclusion about variant significance. c.896G>A has been reported in the literature in multiple bi-alleleic individuals affected with Oculocutaneous Albinism (example: Lin_2014). Other Variants affecting this residue (p.Arg299Ser, p.Arg299Cys) have been classified pathogenic in ClinVar. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24721949). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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
Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.	Shahzad M	Scientific reports	2017	PMID: 28266639
Identification of a missense mutation in the tyrosinase gene in a Chinese family with oculocutaneous albinism type 1.	Lu Q	Molecular medicine reports	2017	PMID: 28112372
Mutational Analysis of the TYR and OCA2 Genes in Four Chinese Families with Oculocutaneous Albinism.	Wang Y	PloS one	2015	PMID: 25919014
A comprehensive study of oculocutaneous albinism type 1 reveals three previously unidentified alleles on the TYR gene.	Lin YY	European journal of dermatology : EJD	2014	PMID: 24721949
A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism.	Wei A	The Journal of investigative dermatology	2010	PMID: 19865097
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 rs61754375 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000372.5(TYR):c.896G>A (p.Arg299His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61754375 ...