ClinVar Miner

Submissions for variant NM_000372.5(TYR):c.665T>C (p.Ile222Thr)

gnomAD frequency: 0.00096  dbSNP: rs34878847
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000592113 SCV000705338 uncertain significance not provided 2017-01-05 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001109648 SCV001267009 uncertain significance Oculocutaneous albinism 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000592113 SCV001693497 pathogenic not provided 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 222 of the TYR protein (p.Ile222Thr). This variant is present in population databases (rs34878847, gnomAD 0.3%). This missense change has been observed in individual(s) with oculocutaneous albinism (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 499705). 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.
Genome-Nilou Lab RCV001591355 SCV001821904 likely benign Tyrosinase-negative oculocutaneous albinism 2021-07-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821726 SCV002070570 uncertain significance not specified 2018-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821726 SCV005202470 uncertain significance not specified 2024-07-30 criteria provided, single submitter clinical testing Variant summary: TYR c.665T>C (p.Ile222Thr) 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 0.00014 in 1612468 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00014 vs 0.0056), allowing no conclusion about variant significance. c.665T>C has been reported in the literature in at least one heterozygous individual affected with Oculocutaneous Albinism without detected second variant (e.g. Gao_2017). This report does not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28451379, 23504663). ClinVar contains an entry for this variant (Variation ID: 499705). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV005010575 SCV005631342 likely pathogenic Tyrosinase-negative oculocutaneous albinism; Oculocutaneous albinism type 1B; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN 2024-04-08 criteria provided, single submitter clinical testing

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