Submissions for variant NM_000372.5(TYR):c.1467dup (p.Ala490fs)

gnomAD frequency: 0.00014  dbSNP: rs61754399

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085926	SCV000343460	pathogenic	not provided	2016-07-19	criteria provided, single submitter	clinical testing	The c.1467dupT pathogenic variant has been reported in individuals with oculocutaneous albinism1-3 and is of a type expected to cause disease.[1-3] 1. Chintamaneni et al., Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5272-6. 2. King et al., Hum Genet. 2003 Nov;113(6):502-13. 3. Grønskov et al., Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1058-64.
Genetic Services Laboratory, University of Chicago	RCV000004007	SCV000597800	pathogenic	Tyrosinase-negative oculocutaneous albinism	2017-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000085926	SCV001820278	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 40 amino acids are lost and replaced with 19 incorrect amino acids in published literature (Chintamaneni et al., 1991); Published functional studies demonstrate c.1467dupT impairs the C-terminus of the protein and reduces enzyme activity (Chintamaneni et al., 1991); This variant is associated with the following publications: (PMID: 13680365, 1711223, 28667292, 19060277, 1642278, 28451379, 18821858, 18463683, 1409426, 15146472, 34426522, 26689913, 28976636, 18326704)
Genome-Nilou Lab	RCV000004007	SCV001821974	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085926	SCV002185701	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala490Cysfs*20) in the TYR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the TYR protein. This variant is present in population databases (rs543973275, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with oculocutaneous albinism (PMID: 1642278, 1711223, 13680365, 18463683). ClinVar contains an entry for this variant (Variation ID: 3803). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000004007	SCV002580654	likely pathogenic	Tyrosinase-negative oculocutaneous albinism	2022-01-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496251	SCV002810512	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085926	SCV003823780	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV003225016	SCV003922022	pathogenic	Oculocutaneous albinism type 1B	2023-02-17	criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with c.[575C>A;1205G>A] variants (hypomorphic allele)
Institute of Human Genetics, University of Leipzig Medical Center	RCV003225016	SCV004027782	pathogenic	Oculocutaneous albinism type 1B	2023-05-17	criteria provided, single submitter	clinical testing	Identified as compund heterozygous with NM_000372.5:c.1205G>A. Criteria applied: PM3_VSTR,PVS1_MOD
Baylor Genetics	RCV003466804	SCV004207547	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782008	SCV005395062	pathogenic	Oculocutaneous albinism	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: TYR c.1467dupT (p.Ala490CysfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00018 in 251060 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism, allowing no conclusion about variant significance. c.1467dupT has been reported in the literature in multiple compound heterozygous individuals affected with Oculocutaneous Albinism (e.g. King_2003, Gao_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28451379, 13680365). ClinVar contains an entry for this variant (Variation ID: 3803). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004007	SCV000024173	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085926	SCV000118069	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000085926	SCV001921759	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085926	SCV001965901	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739290	SCV005363828	pathogenic	TYR-related disorder	2024-07-26	no assertion criteria provided	clinical testing	The TYR c.1467dupT variant is predicted to result in a frameshift and premature protein termination (p.Ala490Cysfs*20). This variant has been reported in the compound heterozygous state in individuals with oculocutaneous albinism (King et al. 2003. PubMed ID: 13680365; Norman et al. 2017. PubMed ID: 28667292; Marti et al. 2018. PubMed ID: 28976636). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in TYR are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3803). Given the evidence, we interpret this variant as pathogenic.