ClinVar

Description

The c.42G>A variant in MYOC is a synonymous variant (p.Glu14=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the <=0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. This variant was not predicted to affect splicing, as assessed with SpliceAI (<=0.2), with a CADD score (v1.6) = 4.764 which met the <=10 threshold for BP4, and the GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 probands with juvenile open angle glaucoma have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (>=2 probands). In summary, this variant met the criteria to receive a score of 0 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, BP7, PS4_Supporting. PM2_Supporting.