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

gnomAD frequency: 0.00051  dbSNP: rs61754388

Total submissions: 23

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	RCV000003973	SCV000245677	pathogenic	Tyrosinase-negative oculocutaneous albinism	2014-08-22	criteria provided, single submitter	clinical testing	The Thr373Lys variant in TYR has been reported in >40 individuals with autosomal recessive oculocutaneous albinism type I and was found to segregate with disease in 3 affected relatives from 1 family (OCA1; Spritz 1990, Gershoni-Baruch 1994, King 2003, Opitz 2004, Hutton 2008, Hutton 2008, Cargiulo 2011). This variant has been identified in 0.08% (7/8596) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs61754388). 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), however these types of assays may not accurately represent biological function. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
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	2022-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085898	SCV001248574	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TYR: PM3:Very Strong, PM2, PP4, PS3:Supporting
Invitae	RCV000085898	SCV001580868	pathogenic	not provided	2024-01-29	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; 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.
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	RCV000003973	SCV002768421	pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-02-02	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 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
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
PreventionGenetics, part of Exact Sciences	RCV003390638	SCV004109927	pathogenic	TYR-related condition	2023-08-14	criteria provided, single submitter	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, 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.
Baylor Genetics	RCV001542596	SCV004207545	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2023-10-25	criteria provided, single submitter	clinical testing
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