rs61754388

chr11-89227904-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000372.5
• 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/exons	MANE	UniProt
TYR	NM_000372.5	c.1118C>A	p.Thr373Lys	missense_variant	3/5	ENST00000263321.6
TYR	XM_011542970.3	c.1118C>A	p.Thr373Lys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.1118C>A	p.Thr373Lys	missense_variant	3/5	1	NM_000372.5	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152014 Hom.: 0 Cov.: 32

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: 86 AN: 250994 Hom.: 0 AF XY: 0.000413 AC XY: 56 AN XY: 135634

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.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 635 AN XY: 727014

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: 75 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74248

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.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000819

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 10, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 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 segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 05, 2021	- -

not provided Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TYR: PM3:Very Strong, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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; Invitae). 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). 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 not expected to disrupt TYR protein function with a negative predictive value of 80%. 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 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

TYR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 28, 2023	PS3, PM3_Very Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 14, 2023	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, Table 2; Hutton & Spritz. 2008. PubMed ID: 18463683, Table 1). This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88961072-C-A). 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 c.1118C>A (p.Thr373Lys) as pathogenic. -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Oculocutaneous albinism type 1B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Oct 10, 2022

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. -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	24
Dann	Uncertain	0.97
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	0.049
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0010	B
Vest4		0.77
MVP		1.0
MPC		0.011
ClinPred		0.27	T
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

Other links and lift over

dbSNP: rs61754388; hg19: chr11-88961072;