ClinVar

Description

The c.1290C>T variant in MYOC is a synonymous variant (p.Phe430=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (<=0.0001) or the BS1 allele frequency threshold (>=0.001). The CADD score (v1.6) = 6.961, which met the <=10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (<=0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 2.25 (threshold < 0), 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 juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the >=2 probands threshold required to meet PS4_Supporting. 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4.