Submissions for variant NM_000372.5(TYR):c.1037-1G>A

gnomAD frequency: 0.00002  dbSNP: rs61754382

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500289	SCV000597796	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-08-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000500289	SCV001821959	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085888	SCV002240381	pathogenic	not provided	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the TYR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TYR are known to be pathogenic (PMID: 23504663). This variant is present in population databases (rs61754382, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with oculocutaneous albinism (PMID: 9259202, 18326704, 27734839, 31077556). This variant is also known as IVS2-1G>A. ClinVar contains an entry for this variant (Variation ID: 99526). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505019	SCV002804578	likely pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460772	SCV004207608	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-02-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000085888	SCV004563951	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	The TYR c.1037-1G>A variant (rs61754382) is reported in the literature in the compound heterozygous state in several individuals affected with oculocutaneous albinism (Jackson 2020, Spritz 1997). This variant is reported in ClinVar (Variation ID: 99526). This variant is only observed on five alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 2, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Jackson D et al. Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom. Am J Med Genet C Semin Med Genet. 2020 Sep;184(3):578-589. PMID: 32830442. Spritz RA et al. Novel mutations of the tyrosinase (TYR) gene in type I oculocutaneous albinism (OCA1). Hum Mutat. 1997;10(2):171-4. PMID: 9259202.
GeneDx	RCV000085888	SCV005325011	pathogenic	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18326704, 25525159, 9259202, 28451379, 31980526)
Retina International	RCV000085888	SCV000118031	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004739346	SCV005362323	pathogenic	TYR-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The TYR c.1037-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported along with a second TYR variant in individual with oculocutaneous albinism (denoted as IVS2-1G>A, Spritz et al. 1997. PubMed ID: 9259202; Hutton et al. 2008. PubMed ID: 18326704). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in TYR are expected to be pathogenic. This variant is interpreted as pathogenic.