ClinVar Genomic variation as it relates to human health

The c.1153G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 385 (p.Glu385Lys). 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. The REVEL score = 0.948, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 31653660), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 31653660), not meeting the >= 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 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): PP1, PP3, PM2_Supporting.

The heterozygous p.E385K variant was identified in a multi-generation family affected by glaucoma: three affected siblings and their affected father had onset of glaucoma before age 30, and all 4 individuals were identified to have this variant. There were no unaffected siblings of these individuals, thus segregation data is limited. The paternal grandfather of the siblings did not have glaucoma and also did not have the p.E385K variant. Other additional family members were known to have glaucoma but were deceased or otherwise unavailable for testing. This missense variant is absent from gnomAD. p.E385 is highly conserved in evolution, and p.E385K has multiple lines of computational evidence supporting a deleterious effect and a CADD score greater than 20.