ClinVar

Description

The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the >= 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.257, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate.