Submissions for variant NM_000372.5(TYR):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00006  dbSNP: rs28940881

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193173	SCV000249335	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-04-17	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626675	SCV000747378	pathogenic	Horizontal nystagmus; Hypopigmentation of the skin; Hypopigmentation of hair; Iris transillumination defect	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626676	SCV000747379	pathogenic	Albinism; Nystagmus; Myopia	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626677	SCV000747380	pathogenic	Foveal hypoplasia; Albinism; Abnormality of metabolism/homeostasis; Elevated circulating hepatic transaminase concentration; Slow decrease in visual acuity; Choroidal neovascularization	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763286	SCV000893933	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; Ocular albinism with congenital sensorineural hearing loss; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2018-10-31	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001836693	SCV000927076	pathogenic	Abnormality of the skin	2021-07-10	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000193173	SCV001366304	pathogenic	Tyrosinase-negative oculocutaneous albinism	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP4,PS1.
Genome-Nilou Lab	RCV000193173	SCV001821914	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000085931	SCV001982608	pathogenic	not provided	2024-11-16	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34897530, 7704033, 7955413, 36460718, 34426522, 28976636, 31077556, 31589614, 28378818, 30219046)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085931	SCV002239438	pathogenic	not provided	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the TYR mRNA. The next in-frame methionine is located at codon 31. This variant is present in population databases (rs28940881, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with oculocutaneous albinism type (PMID: 7955413, 28378818, 28976636, 31077556). ClinVar contains an entry for this variant (Variation ID: 3807). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002466393	SCV002761836	likely pathogenic	Oculocutaneous albinism	2021-04-29	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000004011	SCV004047869	pathogenic	Oculocutaneous albinism type 1B		criteria provided, single submitter	clinical testing	The initiator codon variant p.M1V in TYR (NM_000372.5) has been previously reported in individuals affected with Ocular albinism ( Fukaiet al, 1995). The p.M1V variant is observed in 15/1,13,732 (0.0132%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.M1V variant is a loss of function variant in the gene TYR, which is intolerant of Loss of Function variants. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The nucleotide change in TYR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
Neuberg Centre For Genomic Medicine, NCGM	RCV000193173	SCV005042598	pathogenic	Tyrosinase-negative oculocutaneous albinism		criteria provided, single submitter	clinical testing	The start lost c.1A>G p.Met1? variant in TYR gene has been reported previously in individuals affected in both homozygous and compound heterozygous state with oculocutaneous albinism type A Baban et al. 2018; Zhong et al. 2019. The p.Met1? variant is reported with an allele frequency of 0.006% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submissions. The amino acid change p.Met1? in TYR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The next in-frame methionine is located at codon 31. The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004011	SCV005368313	pathogenic	Oculocutaneous albinism type 1B	2024-08-20	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_MOD,PM3_VSTR,PS1,PP4
OMIM	RCV000004011	SCV000024177	pathogenic	Oculocutaneous albinism type 1B	1995-01-01	no assertion criteria provided	literature only
Retina International	RCV000085931	SCV000118074	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000085931	SCV001926096	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085931	SCV001954191	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739291	SCV005364101	pathogenic	TYR-related disorder	2024-08-01	no assertion criteria provided	clinical testing	The TYR c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the compound heterozygous state in individuals with oculocutaneous albinism (Fukai et al. 1995. PubMed ID: 7704033; Breimer et al. 1994. PubMed ID: 7955413; Marti et al. 2018. PubMed ID: 28976636). This variant is reported in 0.012% 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/3807/). Given all the evidence, we interpret this variant as pathogenic.