rs61754388

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000372.5(TYR):c.1118C>A(p.Thr373Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000882 in 1,613,434 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T373A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 1 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 5.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89227903-A-G is described in Lovd as [Pathogenic].

PP5

Variant 11-89227904-C-A is Pathogenic according to our data. Variant chr11-89227904-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89227904-C-A is described in Lovd as [Pathogenic]. Variant chr11-89227904-C-A is described in Lovd as [Likely_pathogenic]. Variant chr11-89227904-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.1118C>A	p.Thr373Lys	missense_variant	Exon 3 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.1118C>A	p.Thr373Lys	missense_variant	Exon 3 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.1118C>A	p.Thr373Lys	missense_variant	Exon 3 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000971

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000343

AC:

AN:

250994

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000687

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000922

AC:

1348

AN:

1461420

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

635

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.000493

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000971

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000802

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000819

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 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, PP4, PS3:Supporting -

Jan 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, specifically, T373K transfected cells had no tyrosine hydroxylase activity, undetectable melanin production, and showed the T373K mutant protein was unable to leave the endoplasmic reticulum (Tripathi et al., 1992; Toyofuku et al., 2001). A separate in vitro study also suggests improper folding of the T373K protein (Dolinska et al., 2017); 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: 9242509, 11284711, 23085273, 2342539, 27775880, 28484254, 1429711, 27535533, 18463683, 29036293, 28555837, 25533962, 31233279, 31719542, 28976636, 32543925, 31980526, 31589614, 33077847) -

Mar 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 373 of the TYR protein (p.Thr373Lys). This variant is present in population databases (rs61754388, gnomAD 0.07%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 2342539, 9259202, 13680365, 18326704; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as Thr355Lys. ClinVar contains an entry for this variant (Variation ID: 3774). 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. Experimental studies have shown that this missense change affects TYR function (PMID: 1429711, 9242509, 27775880). For these reasons, this variant has been classified as Pathogenic. -

Oculocutaneous albinism type 1A

Pathogenic:7

Nov 05, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: 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

- -

Oct 10, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This TYR variant (rs61754388) is rare (<0.1%) in a large population dataset (gnomAD: 100/282382 total alleles; 0.035%; no homozygotes) and has been reported in ClinVar. It is one of the most commonly reported TYR variants in individuals of European ancestry with OCA1. This variant has been observed in a homozygous or compound heterozygous state with another pathogenic TYR variant and has been shown to segregate with disease in affected families. This amino acid substitution (p.Thr373Lys) disrupts a signal for N-glycosylation, which results in incomplete processing of the tyrosinase enzyme to its mature glycosylated form and retention of the protein in the endoplasmic reticulum (ER). Experimental studies in transfected HeLa cells demonstrate that the p.Thr373Lys variant abolishes catalytic activity. We consider c.1118C>A to be pathogenic. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism

Pathogenic:4

Jan 15, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr373Lys variant in TYR has been reported in >40 individuals with Oculocutaneous albinism and was found to segregate with disease in 3 affected relatives from 1 family (Spritz 1990, Gershoni-Baruch 1994, King 2003, Opitz 2004, Hutton 2008, Hutton 2008, Cargiulo 2011). It has also been identified in 0.07% (88/128890) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 3774). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies suggest this variant leads to abolished TYR activity (Tripathi 1992). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Oculocutaneous albinism. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3_Moderate. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TYR c.1118C>A (p.Thr373Lys) missense variant has been reported in seven studies in which it is found in a total of 35 patients with oculocutaneous albinism, including in one in a homozygous state, in 29 in a compound heterozygous state (including one sibling pair and three sisters), and in five in a heterozygous state. None of the affected individuals demonstrated detectable tyrosinase activity, with carriers having low activity compared to controls (Spritz et al. 1990; Oetting et al. 1991; Tripathi et al. 1992; Park et al. 1993; Oetting et al. 1993; Hutton et al. 2008; Gargiulo et al. 2011). Segregation of the p.Thr373Lys variant with disease was shown in several of the studies (Spritz RA et al. 1990; Park et al. 1993; Gargiulo et al. 2011). The p.Thr373Lys variant was absent from 26 control alleles but is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. The Thr373 residue is conserved and located in the region of the protein involved in binding copper which is necessary for catalytic activity (Tripathi et al. 1992). Park et al. (1993) showed that the variant protein was not processed to the mature glycosylated form. Immunohistochemistry studies in COS7 cells by Toyofuku et al. (2001) showed that the p.Thr373Lys variant protein is retained in the ER, in contrast to the wild type protein. Transient expression studies in transfected HeLa cells demonstrated that the p.Thr373Lys variant abolished all three catalytic activities associated with the wild type tyrosinase and was unable to produce melanin (Tripathi et al. 1992). Based on the collective evidence, the p.Thr373Lys variant is classified as pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Aug 08, 2024

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.1118C>A (p.Thr373Lys) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 250994 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00034 vs 0.0056), allowing no conclusion about variant significance. c.1118C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Albinism (e.g. Lasseaux_2018). 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: 29345414). ClinVar contains an entry for this variant (Variation ID: 3774). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 17, 2023

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, TYR-related (MONDO:0018910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.(Thr373Ala): 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tyrosinase domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with albinism or ocular albinism (ClinVar, PMIDs: 2342539, 18326704, 29345414). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been identified in a family with at least four affected individuals (PMID: 2342539). (SP) 1205 - This variant has been shown to be maternally inherited (by carrier screening analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oculocutaneous albinism type 1B

Pathogenic:2

Feb 19, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>A) at position 1118 of the coding sequence of the TYR gene that results in a threonine to lysine amino acid change at residue 373 of the tyrosinase protein. The 373 residue falls in the tyrosinase domain (UniProt). This is a previously reported variant (ClinVar 3774) and is one of the most common variants associated oculocutaneous albinism in both the homozygous and compound heterozygous states (PMID: 1642278, 13680365, 27734839, 30472657, 15146472, 18326704, 23504663, 13680365). This variant is present in 161 of 403008 alleles (0.0399%) in the gnomAD population dataset. Bioinformatic tools provide conflicting predictions concerning the impact of this variant, and the Thr373 residue at this position is highly conserved across the vertebrate species examined. Functional studies have demonstrated that the protein resulting from this variant has nearly no tyrosinase activity, produces nearly no melanin, fails to leave the endoplasmic reticulum, and is degraded (PMID: 11284711, 1429711, 9242509, 27775880). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP2, PS3, PS4 -

Oct 10, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TYR-related disorder

Pathogenic:2

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TYR c.1118C>A variant is predicted to result in the amino acid substitution p.Thr373Lys. This variant has been reported as causative for oculocutaneous albinism when present with a second pathogenic variant (Opitz et al. 2004. PubMed ID: 15146472; King et al. 2003. PubMed ID: 13680365; Hutton & Spritz. 2008. PubMed ID: 18463683). This variant is reported in 0.068% 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/3774/). Given all the evidence, we interpret this variant as pathogenic. -

Jul 28, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Very Strong, PP3 -

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

Pathogenic:2

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

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.1118C>A (p.Thr373Lys) variant has been reported in several individuals affected with oculocutaneous albinism in the compound heterozygous state (Gershoni-Baruch R et al., PMID: 8128955; Hutton SM and Spritz RA, PMID: 18326704; King RA et al., PMID: 13680365). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters. This variant is only observed on 100/282,382 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to TYR function. In support of this prediction, a functional study indicates that the variant protein shows no enzymatic activity (Dolinska MB et al., PMID: 27775880). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Pathogenic

0.96

Eigen

Benign

0.049

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.0010

Vest4

0.77

MVP

1.0

MPC

0.011

ClinPred

0.27

GERP RS

4.5

Varity_R

0.90

gMVP

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over