Submissions for variant NM_000261.2(MYOC):c.654G>A (p.Glu218=)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003148614	SCV003836528	uncertain significance	Open-angle glaucoma	2023-02-15	reviewed by expert panel	curation	The c.654G>A variant in MYOC is a synonymous variant (p.Glu218=). Although this variant was not found in gnomAD (v2.1.1), the population from which the variant had been reported (South African) was not well represented in this dataset and the variant has been reported in controls (PMID: 21552496). Thus PM2_Supporting was not applied to this variant. The CADD score (v1.6) = 8.018, which met the <=10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (<=0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 0.511 (threshold <0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with primary open angle glaucoma have been reported carrying this variant (PMID: 21552496), PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4