Submissions for variant NM_000372.5(TYR):c.1118C>A (p.Thr373Lys)

gnomAD frequency: 0.00051  dbSNP: rs61754388

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085898	SCV000228863	pathogenic	not provided	2017-03-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000335429	SCV000245677	pathogenic	Oculocutaneous albinism	2020-01-15	criteria provided, single submitter	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.
Genetic Services Laboratory, University of Chicago	RCV000003973	SCV000249332	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-06-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000085898	SCV000329959	pathogenic	not provided	2022-01-17	criteria provided, single submitter	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)
Illumina Laboratory Services, Illumina	RCV000335429	SCV000374874	pathogenic	Oculocutaneous albinism	2017-04-27	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV002476920	SCV000611335	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085898	SCV001248574	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TYR: PM3:Very Strong, PM2, PP4, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085898	SCV001580868	pathogenic	not provided	2025-02-03	criteria provided, single submitter	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.
Genome-Nilou Lab	RCV000003973	SCV001821962	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000003973	SCV002556367	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-11-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000003973	SCV002581133	pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-07-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000335429	SCV002768421	pathogenic	Oculocutaneous albinism	2023-07-17	criteria provided, single submitter	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
Johns Hopkins Genomics, Johns Hopkins University	RCV000003973	SCV003839048	pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-10-10	criteria provided, single submitter	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150806	SCV003839049	pathogenic	Oculocutaneous albinism type 1B	2022-10-10	criteria provided, single submitter	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387500	SCV004099263	pathogenic	TYR-related disorder	2023-07-28	criteria provided, single submitter	clinical testing	PS3, PM3_Very Strong, PP3
Baylor Genetics	RCV001542596	SCV004207545	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000003973	SCV004814164	pathogenic	Tyrosinase-negative oculocutaneous albinism	2024-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000335429	SCV005380799	pathogenic	Oculocutaneous albinism	2024-08-08	criteria provided, single submitter	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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV003150806	SCV005397661	pathogenic	Oculocutaneous albinism type 1B	2024-02-19	criteria provided, single submitter	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
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005054134	SCV005688756	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B	2024-09-22	criteria provided, single submitter	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.
OMIM	RCV000003973	SCV000024138	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085898	SCV000118041	not provided	not provided		no assertion provided	not provided
Genomics England Pilot Project, Genomics England	RCV001542596	SCV001760288	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000085898	SCV001925021	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085898	SCV001954491	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085898	SCV001964975	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003387500	SCV004109927	pathogenic	TYR-related disorder	2024-05-02	no assertion criteria provided	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.