Variant: NM_000261.2:c.654G>A

CA421783387

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 4567d3b1-e274-4b15-8fcb-6b17274b9dac

HGVS expressions

NM_000261.2:c.654G>A
NC_000001.11:g.171638673C>T
CM000663.2:g.171638673C>T
NC_000001.10:g.171607813C>T
CM000663.1:g.171607813C>T
NC_000001.9:g.169874436C>T
NG_008859.1:g.18961G>A
ENST00000037502.11:c.654G>A
ENST00000637303.1:c.278C>T
ENST00000638471.1:c.184G>A
ENST00000037502.10:c.654G>A
ENST00000614688.1:c.654G>A
NM_000261.1:c.654G>A

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: BS3 BS1 BP7 BA1 PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 PM6 PM2

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

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

Met criteria codes

• BP4: 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.

Not Met criteria codes

• BS3: No functional evidence has been found for this variant.
• BS1: See comment for PM2_Supporting.
• BP7: Although this synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 0.511 (threshold <0), indicating conservation at this site.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• PS3: No functional evidence has been found for this variant.
• PS4: Although probands with POAG have been reported carrying this variant (PMID: 21552496), PM2_Supporting was not met, therefore PS4 did not apply.
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• PM6: This variant has not been identified de novo.
• PM2: 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.

Approved on: 2023-02-15

Published on: 2023-02-15