ClinVar Genomic variation as it relates to human health

The TYR c.650G>A (p.Arg217Gln) missense variant has been reported in at least three studies and is found in a compound heterozygous state in at least five individuals with oculocutaneous albinism, with at least one individual carrying a pathogenic variant in trans (Wang et al. 2005; Hutton and Spritz 2008; Grønskov et al. 2009). The variant was not found in 50 healthy unrelated control individuals (Grønskov et al. 2009) and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two additional variants in the Arg217 residue (p.Arg217Trp and p.Arg217Gly) have been reported in individuals with oculocutaneous albinism in a compound heterozygous state (Hutton and Spritz 2008). Based on the evidence, the p.Arg217Gln variant is classified as likely pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 217 of the TYR protein (p.Arg217Gln). This variant is present in population databases (rs61754365, gnomAD 0.06%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 10987646, 28976636, 29345414). 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: 99575). 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 not expected to disrupt TYR protein function with a negative predictive value of 80%. This variant disrupts the p.Arg217 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1642278, 10987646, 27734839, 28266639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

TYR: PM3:Very Strong, PM1, PM2, PM5, PP4

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34897530, 32966289, 8477259, 13680365, 19208379, 28976636, 28451379, 18463683, 31233279, 16170149, 19060277, 28629449, 31980526, 33050356, 34426522, 31589614, 34838614, 9259202)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099575). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in multiple similarly affected unrelated individuals (PMID: 18463683 , 27734839). A different missense change at the same codon (p.Arg217Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.