MYOC p.Pro481Arg

The c.1442C>G variant in MYOC is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 481 (p.Pro481Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.853, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 12789574), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1442C>T, p.Pro481Leu, Grantham score = 98, PMID: 10196380) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1442C>G, p.Pro481Arg variant has a higher Grantham score (= 103) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting, PM5_Supporting