rs1126809

Description

The variant TYR:c.1205G>A (p.Arg402Gln) was identified in dbSNP (ID: rs1126809) and ClinVar. The variant was identified in ClinVar with conflicting classifications (classified as pathogenic by OMIM, classified as likely pathogenic by the Centre for Mendelian Genomics, classified as uncertain significance by EGL Genetic Diagnostics, classified as likely benign by Illumina Clinical Services Laboratory, classified as benign by GeneReviews and PreventionGenetics). In one study, 122 patients had one pathogenic variant of the TYR gene and the p.Arg402Gln variant within a cohort of 268 patients diagnosed with oculocutaneous albinism type 1 (OCA1), emphasizing in favour of p.Arg402Gln being a mildly pathogenic TYR variant when associated in trans with another pathogenic variant (Monferme_2018_30472657). In another study, 2 patients in a cohort of 12 presenting with autosomal recessive ocular albinism (AROA) were each a compound heterozygote for a different pathologic mutant allele and an allele containing a ‘normal’ polymorphism, Arg402Gln. In these patients, AROA thus appears to represent a clinically mild form of OCA1 (Fukai_1995_7704033). Another study involving the clinical diagnosis of 30 Iranian OCA1 patients detected 6 patients with the heterozygous p.Arg402Gln variant, with two of those patients heterozygous for one other reported missense mutation in the TYR gene (Kalahroudi_2014_ 25216246). In another cohort with 18 probands categorized as having hypomorphic albinism, 6 had inherited the p.Arg402Gln variant in addition to another common TYR variant, p.Ser192Tyr (Norman_2017_28667292). The variant was identified in control databases in 49,703 of 281,606 chromosomes (5,932 homozygous) at a frequency of 17.6498%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 3501 of 128,366 chromosomes (freq: 4,795) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Arg402Gln residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

DNA sequence analysis of the TYR gene demonstrated a sequence change, c.1205G>A, in exon 4 that results in an amino acid change, p.Arg402Gln. The p.Arg402Gln substitution is a well-documented temperature-sensitive reduced function allele that alone is not sufficient to cause an oculocutaneous albinism phenotype. However, the p.Arg402Gln substitution, if found in compound heterozygous state with a pathogenic mutation, may be associated with a mild oculocutaneous albinism type 1B (OCA1B) or ocular albinism (OA) phenotype (PMIDs: 7704033, 19938076, 18463683, 18326704, 23504663). The p.Arg402Gln substitution has been described in the gnomAD database with a high population frequency of 28% in the European American population (dbSNP rs1126809). Some studies have suggested that the p.Arg402Gln substitution is not associated with mild OCA1B or OA phenotype, due to its high frequency in the general population and the presence of this variant in trans with a pathogenic variant in unaffected parents (PMID: 19208379). It has been proposed that the p.Arg402Gln variant causes a partial albinism phenotype only when paired with certain genetic backgrounds (PMIDs: 7704033, 19938076) and multiple studies have shown that the p.Arg402Gln variant is more common in OCA patients with one TYR pathogenic variant than in patients with two pathogenic variants (PMIDs: 18463683, 18326704, 19938076, 23504663).

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP3,PP4,PP5,BA1. This variant was detected in homozygous state.

Autosomal recessive ocular albinism (AROA) has been linked to compound heterozygosity of TYR mutations with Arg402Gln. Arg402Gln has been shown to encode for a tyrosinase with reduced thermal stability suggesting a hypomorphic effect. The variant has reduced penetrance as there exists a discrepancy between expected incidence of Arg402Gln compound heterozygotes and AROA prevalence. Segregation studies have also revealed unaffected compound heterozygotes suggesting there are additional factors contributing to the AROA condition. Population allele frequency is high (gnomAD AF 0.19287) and there are unaffected homozygotes.