ClinVar Genomic variation as it relates to human health

The c.1130C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 377 (p.Thr377Met). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.00006152 (1 allele out of 16 256), which met the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.924, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, as the results were conflicting and inconclusive, PS3 was not applied. 47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (>=7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (>= 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification >= 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PP3, PM2_Supporting

PS4, PM2, PM5, PP3, PP5