Submissions for variant NM_000372.5(TYR):c.230G>A (p.Arg77Gln)

gnomAD frequency: 0.00006  dbSNP: rs61753185

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000003975	SCV000249336	pathogenic	Tyrosinase-negative oculocutaneous albinism	2015-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000085934	SCV000779692	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: abnormal protein folding and no in vitro enzyme activity (Dolinksa et al., 2017); This variant is associated with the following publications: (PMID: 23324268, 2113511, 1642278, 32552793, 10929771, 32427313, 21985232, 34487524, 27775880, 31077556, 28976636)
Eurofins Ntd Llc (ga)	RCV000085934	SCV000855376	pathogenic	not provided	2017-07-12	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000003975	SCV000890897	pathogenic	Tyrosinase-negative oculocutaneous albinism	2017-02-09	criteria provided, single submitter	clinical testing
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000003975	SCV000996277	pathogenic	Tyrosinase-negative oculocutaneous albinism		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003975	SCV001524703	pathogenic	Tyrosinase-negative oculocutaneous albinism	2020-01-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000003975	SCV001821923	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085934	SCV002139732	pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 77 of the TYR protein (p.Arg77Gln). This variant is present in population databases (rs61753185, gnomAD 0.01%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 21985232, 31077556). ClinVar contains an entry for this variant (Variation ID: 3776). 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) indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TYR function (PMID: 21985232). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000085934	SCV002497161	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476921	SCV002785299	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2022-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085934	SCV003823791	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156054	SCV003845333	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466800	SCV004207559	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-11	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003466800	SCV004801134	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-14	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782006	SCV005395371	pathogenic	Oculocutaneous albinism	2024-09-19	criteria provided, single submitter	clinical testing	Variant summary: TYR c.230G>A (p.Arg77Gln) results in a conservative amino acid change in 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 8.4e-05 in 251030 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (8.4e-05 vs 0.0056), allowing no conclusion about variant significance. c.230G>A has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (example, Shah_2015,Takeda_1989). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished catalytical activity in mouse amelanotic melanoma cells (Takeda_1989). The following publications have been ascertained in the context of this evaluation (PMID: 25703744, 2120217). ClinVar contains an entry for this variant (Variation ID: 3776). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000003975	SCV000024140	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085934	SCV000118077	not provided	not provided		no assertion provided	not provided
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000984954	SCV001132868	pathogenic	Oculocutaneous albinism type 1B	2019-01-29	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000003975	SCV001132869	pathogenic	Tyrosinase-negative oculocutaneous albinism	2019-01-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532282	SCV004114465	pathogenic	TYR-related disorder	2024-07-26	no assertion criteria provided	clinical testing	The TYR c.230G>A variant is predicted to result in the amino acid substitution p.Arg77Gln. This variant has been reported in the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (see for examples Kikuchi et al. 1990. PubMed ID: 2113511; Kono et al. 2012. PubMed ID: 21985232; Marti et al. 2018. PubMed ID: 28976636). Functional studies support the pathogenicity of this variant (Dolinska et al. 2017. PubMed ID: 27775880; Kono et al. 2012. PubMed ID: 219852320). 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/3776/). Given all the evidence, we interpret this variant as pathogenic.