11-89178602-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM5PP2PP5

The NM_000372.5(TYR):c.649C>T(p.Arg217Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,612,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:1O:1

Conservation

PhyloP100: 0.182

Publications

12 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000372.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89178603-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 99575.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.

PP5

Variant 11-89178602-C-T is Pathogenic according to our data. Variant chr11-89178602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3795.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.649C>T	p.Arg217Trp	missense_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3 link	c.649C>T	p.Arg217Trp	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.649C>T	p.Arg217Trp	missense_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1 link	n.710C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000179

AC:

AN:

250756

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1460402

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

726410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.000202

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000464

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000185

AC:

206

AN:

1111116

Other (OTH)

AF:

0.000332

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000118

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41424

American (AMR)

AF:

0.000131

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.000176

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

May 08, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8477259, 1642278, 7963676, 13680365, 25216246, 28266639, 19626598, 18463683, 31589614, 36011402, 34426522, 33800529, 31816670) -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 217 of the TYR protein (p.Arg217Trp). This variant is present in population databases (rs63159160, gnomAD 0.04%). This missense change has been observed in individual(s) with ocular albinism (PMID: 1642278, 10987646, 27734839, 28266639). 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: 3795). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYR protein function. For these reasons, this variant has been classified as Pathogenic. -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TYR: PM3:Very Strong, PM2, PM5 -

Oculocutaneous albinism type 1A

Pathogenic:3

Jul 22, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism type 1B;C4551504:Oculocutaneous albinism type 1A

Pathogenic:2

Sep 22, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TYR c.649C>T (p.Arg217Trp) variant has been reported in several individuals affected with oculocutaneous albinism in the compound heterozygous state (Mauri L et al., PMID: 27734839; Passmore LA et al., PMID: 10987646; Shahzad M et al., PMID: 28266639). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by several submitters and a variant of uncertain significance by one submitter. This variant is only observed on 54/282,142 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on TYR function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM3_VeryStrong+PP4 -

Oculocutaneous albinism

Pathogenic:1

Jul 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TYR c.649C>T (p.Arg217Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00018 in 250756 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00018 vs 0.0056), allowing no conclusion about variant significance. c.649C>T has been observed in multiple individuals affected with Oculocutaneous Albinism (examples, Tripathi_1992, Lasseaux_2017, Shahzad_2017). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.650G>A, p.Arg217Gln), supporting the critical relevance of codon 217 to TYR protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29345414, 28266639, 1642278). ClinVar contains an entry for this variant (Variation ID: 3795). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A;CN028925:Ocular albinism with congenital sensorineural hearing loss

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic Oculocutaneous Albinism

Pathogenic:1

Mar 07, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

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

Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism type 1

Pathogenic:1

May 23, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The following ACMG criteria has been used: PS4_mod, PM3_str, PM2_sup -

Oculocutaneous albinism type 1B

Uncertain:1

Apr 11, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported as disease-causing [PMID 1642278, 28266639, 1903591, 27775880, 25333069, 21906913, 28667292, 24123366, 9242509, 11284711, 1429711] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.10

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.70

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

1.1

PhyloP100

0.18

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.66

REVEL

Uncertain

0.59

Sift

Benign

0.20

Sift4G

Benign

0.19

Polyphen

0.96

Vest4

0.30

MVP

0.99

MPC

0.043

ClinPred

0.082

GERP RS

2.2

Varity_R

0.10

gMVP

0.88

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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