ClinVar

Description

The c.423C>T variant in MYOC is a synonymous variant (p.Ala141=). 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. Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (<=0.2), it had a CADD score (v1.6) = 10.85, which did not meet the <=10 threshold for BP4 and a GERP score = 5.77 (threshold <0), not meeting BP7 and indicating conservation at this site. 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: 23922489). Although at least one variant carrier had been identified in another study (PMID: 20664688), it was not clear as to how many there were, and whether they had open angle glaucoma or not. Thus the >=2 probands threshold required for PS4_Supporting was not met. In summary, this variant met the criteria to receive a score of 1 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): PM2_Supporting