Submissions for variant NM_000372.5(TYR):c.896G>A (p.Arg299His)

gnomAD frequency: 0.00006  dbSNP: rs61754375

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085979	SCV000336496	pathogenic	not provided	2015-11-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000004000	SCV000597793	pathogenic	Tyrosinase-negative oculocutaneous albinism	2017-01-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000004000	SCV001821950	pathogenic	Tyrosinase-negative oculocutaneous albinism	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085979	SCV002022494	pathogenic	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085979	SCV002238914	pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 299 of the TYR protein (p.Arg299His). This variant is present in population databases (rs61754375, gnomAD 0.03%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1642278, 28112372, 28266639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3796). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000085979	SCV003798709	pathogenic	not provided	2021-07-25	criteria provided, single submitter	clinical testing	Reported as one of the most common pathogenic variants in the TYR gene among individuals of Chinese background (Wei et al., 2010); 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: 26165494, 20447099, 32552135, 1642278, 25919014, 19865097, 28112372, 22294196, 28266639, 30833958, 31199599, 30558096, 31077556, 32966289, 33124154, 31589614)
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156055	SCV003845218	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460423	SCV004207538	pathogenic	SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-03-28	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV003488321	SCV004232709	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B	2023-10-31	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492282	SCV004241997	pathogenic	Oculocutaneous albinism	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: TYR c.896G>A (p.Arg299His) results in a non-conservative amino acid change located in the Tyrosinase copper-binding domain (IPR002227) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (6.8e-05 vs 0.0056), allowing no conclusion about variant significance. c.896G>A has been reported in the literature in multiple bi-alleleic individuals affected with Oculocutaneous Albinism (example: Lin_2014). Other Variants affecting this residue (p.Arg299Ser, p.Arg299Cys) have been classified pathogenic in ClinVar. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24721949). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003488321	SCV005418444	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B		criteria provided, single submitter	clinical testing	PP3+PM3_VeryStrong+PP4+PM5_Strong+PM2_Supporting
Fulgent Genetics, Fulgent Genetics	RCV005007819	SCV005631358	pathogenic	Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN	2024-05-24	criteria provided, single submitter	clinical testing
OMIM	RCV000004000	SCV000024166	pathogenic	Tyrosinase-negative oculocutaneous albinism	1992-07-15	no assertion criteria provided	literature only
Retina International	RCV000085979	SCV000118122	not provided	not provided		no assertion provided	not provided
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755072	SCV000882890	likely pathogenic	Nonsyndromic Oculocutaneous Albinism	2017-03-07	no assertion criteria provided	research