ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs61754375
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Total submissions: 13
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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
Invitae RCV000085979 SCV002238914 pathogenic not provided 2024-01-11 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 80%. 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 2023-10-29 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.
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

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