MYOC p.Ser341Pro

The c.1021T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 341 (p.Ser341Pro). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.821, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. A transgenic mouse model carrying human MYOC Ser341Pro (PMID: 38212635), and displaying reduced secretion of the Ser341Pro protein in vivo, exhibited a glaucoma phenotype (including IOP elevation and retina ganglion cell loss), meeting PS3. 12 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17867509, 24825108, 33214997, 25777973), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were more family studies published than presented here. 8 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9510647, 24825108, 25777973, 33214997, 17867509, ClinVar: Invitae), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PS3, PP1_Strong, PS4_Moderate, PP3_Moderate, PM2_Supporting