NM_000372.5:c.242C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000372.5(TYR):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 7.48

Publications

14 publications found

Variant links:

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR Gene-Disease associations (from GenCC):

oculocutaneous albinism type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
oculocutaneous albinism type 1A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Waardenburg syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
minimal pigment oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
oculocutaneous albinism type 1B
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
temperature-sensitive oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TYR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000372.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89178194-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2679408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 116 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.9514 (below the threshold of 3.09). Trascript score misZ: -0.85521 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 2, oculocutaneous albinism type 1A, oculocutaneous albinism type 1, oculocutaneous albinism type 1B, minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 11-89178195-C-T is Pathogenic according to our data. Variant chr11-89178195-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.242C>T	p.Pro81Leu	missense_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3 link	c.242C>T	p.Pro81Leu	missense_variant	Exon 1 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.242C>T	p.Pro81Leu	missense_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1 link	n.303C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000836

AC:

AN:

251066

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000276

AC:

307

AN:

1111988

Other (OTH)

AF:

0.000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000239

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oculocutaneous albinism type 1A

Pathogenic:5

Jul 01, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 03, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with oculocutaneous albinism type IA (MIM#203100) and type IB (MIM#606952). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 26 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants in the TYR gene reported in individuals with OCA1 (PMIDs: 13680365, 18463683, 28451379). Homozygous individuals present with classic OCA1A phenotype (PMID: 1970634). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Homozygous individuals presented no pigment and no detectable tyrosine activity in anagen hairbulbs (PMID: 1970634). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4Other:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TYR: PM3:Very Strong, PM2, PM5, PP4 -

Apr 03, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the TYR protein (p.Pro81Leu). This variant is present in population databases (rs28940876, gnomAD 0.02%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1970634, 8434585, 10987646, 29345414). 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: 3772). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 10987646, 28451379, 1903591, 13680365, 18326704, 1970634, 31233279, 30609409, 31589614, 32581362, 33808351, 8434585, 37327787, 29345414, 34662886) -

TYR-related disorder

Pathogenic:2

Jul 28, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_VeryStrong, PP1, PP3 -

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TYR c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has been reported as a causative variant for oculocutaneous albinism (Giebel et al. 1990. PubMed ID: 1970634; Hutton and Spritz 2008. PubMed ID: 18463683; Ceyhan-Birsoy et al. 2019. PubMed ID: 30609409). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3772). Given all the evidence, we interpret this variant as pathogenic. -

Oculocutaneous albinism

Pathogenic:1

Mar 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro81Leu (NM_000372.4 c.242C>T) variant in TYR has been reported in 4 hete rozygous, 1 homozygous and 7 compound heterozygous individuals with Oculocutaneo us albinism type 1 related disorders (OCA1) (Giebel 1990, King 2003, Opitz 2004, Hutton 2008, Rooryck 2008), segregated in at least 8 family members in 2 famili es (Giebel 2003), and has been reported at pathogenic in ClinVar (Variation ID#3 772). This variant has been identified in 0.015% (10/66458) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs28940876). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . In summary, this variant meets criteria to be classified as pathogenic for OCA 1 in an autosomal recessive manner based upon biallelic case observations and se gregation in affected individuals. -

Oculocutaneous albinism type 1B

Pathogenic:1

Oct 31, 2019

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of the available literature, the TYR c.242C>T (p.Pro81Leu) missense variant has been identified a total of 31 individuals with oculocutaneous albinism type 1, including in three individuals in a homozygous state, in seven individuals in a compound heterozygous state, and in 14 individuals in an assumed compund heterozygous state (Oetting et al. 1991; Giebel et al. 1991; Hutton et al. 2008; King et al. 2013; Goa et al. 2017). The p.Pro81Leu variant was absent from 33 control subjects but is reported at a frequency of 0.000171 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the application of the ACMG criteria, the p.Pro81Leu variant is classified as pathogenic for oculocutaneous albinism type 1. -

Inborn genetic diseases

Pathogenic:1

Oct 03, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.242C>T (p.P81L) alteration is located in exon 1 (coding exon 1) of the TYR gene. This alteration results from a C to T substitution at nucleotide position 242, causing the proline (P) at amino acid position 81 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.009% (26/282452) total alleles studied. The highest observed frequency was 0.017% (22/128894) of European (non-Finnish) alleles. This variant has been identified homozygous and likely in trans with a TYR second variant in multiple individuals diagnosed with oculocutaneous albinism (Hutton, 2008; Gao, 2017), as well as in a three individuals from a large family (Giebel, 1990). Another alteration at the same codon, c.241C>T (p.P81S), has been described in one individual with oculocutaneous albinism (King, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A

Pathogenic:1

Nov 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Albinism

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN

Pathogenic:1

Mar 14, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism type 1

Pathogenic:1

Apr 11, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in TYR is predicted to replace proline with leucine at codon 81, p.(Pro81Leu). The proline residue is highly conserved (98/98 vertebrates, UCSC), and is located in the lumenal melanosome domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.02% (22/128,894 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is a commonly reported pathogenic variant and has been detected in multiple individuals with oculocutaneous albinism in the homozygous state and compound heterozygous with a second pathogenic variant in the gene (PMID: 8434585, 28451379). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

PhyloP100

7.5

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.3

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.99

MPC

0.075

ClinPred

1.0

GERP RS

6.1

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.85

gMVP

0.96

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over