ClinVar Genomic variation as it relates to human health

The TYR c.238T>C variant is predicted to result in the amino acid substitution p.Trp80Arg. This variant has been reported along with a second TYR variant in individuals with oculocutaneous albinism (Spritz et al. 1997. PubMed ID: 9259202; King et al. 2003. PubMed ID: 13680365). Additionally, here at PreventionGenetics, we have observed this variant along with a second causative variant in multiple individuals with oculocutaneous albinism (internal data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88911359-T-C). This variant is interpreted as likely pathogenic.

Variant summary: TYR c.238T>C (p.Trp80Arg) results in a non-conservative amino acid change in 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 4e-06 in 251062 control chromosomes. c.238T>C has been reported in the literature in the compound heterozygous state in individuals affected with Oculocutaneous Albinism (e.g. Spritz_1997, King_2002, Kuht_2023, Gao_2017). These data indicate that the variant may be associated with disease. 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, 13680365, 35379600, 9259202). ClinVar contains an entry for this variant (Variation ID: 99556). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 10094567, 9259202, 18463683, 13680365, 23085273)

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 80 of the TYR protein (p.Trp80Arg). This variant is present in population databases (rs61753188, gnomAD 0.0009%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 9259202, 13680365). 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: 99556). 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%. This variant disrupts the p.Trp80 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 13680365, 34838614), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.