Submissions for variant NM_000261.2(MYOC):c.498G>C (p.Leu166=)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003148610	SCV003836524	uncertain significance	Open-angle glaucoma	2023-02-15	reviewed by expert panel	curation	The c.498G>C variant in MYOC is a synonymous variant (p.Leu166=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), which met the <=0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (<=0.2), it had a CADD score (v1.6) = 10.96, which did not meet the <=10 threshold for BP4 and a GERP score = 4.69 (threshold <0), not meeting BP7 and indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 17615537), not meeting the >=2 probands threshold required to meet PS4_Supporting. 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): PM2_Supporting