Variant: NM_000261.2:c.1187_1189dup

CA1139532728

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 20ad1fd9-9eb4-4977-b099-d25f0e06ef1e

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1187_1189dup
NC_000001.11:g.171636252_171636254dup
CM000663.2:g.171636252_171636254dup
NC_000001.10:g.171605392_171605394dup
CM000663.1:g.171605392_171605394dup
NC_000001.9:g.169872015_169872017dup
NG_008859.1:g.21381_21383dup
ENST00000037502.11:c.1187_1189dup
ENST00000637303.1:c.235-2378_235-2376dup
ENST00000638471.1:c.*525_*527dup
ENST00000037502.10:c.1187_1189dup
ENST00000614688.1:c.*151_*153dup
NM_000261.1:c.1187_1189dup

Likely Pathogenic

• Met criteria codes: PS3_Moderate PP1_Moderate PM4_Supporting PM2_Supporting

• Not Met criteria codes: BA1 BP7 BP4 BS3 BS1 PP3 PM6 PM5 PS2 PS1 PS4

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1187_1189dup variant in MYOC is predicted to cause a change in the length of the protein due to an in-frame insertion of 1 amino acid (p.Glu396dup). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. 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. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Glu396dup protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 5 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PM2_Supporting, PM4_Supporting

Met criteria codes

• PS3_Moderate: Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Glu396dup protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.
• PP1_Moderate: 5 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Moderate (5-6 meioses).
• PM4_Supporting: This in-frame insertion variant is predicted to involve ≤10% of the protein and is within the conserved olfactomedin domain.
• PM2_Supporting: 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.

Not Met criteria codes

• BA1: This criterion was not met as PM2_Supporting has been met.
• BP7: This is not a synonymous or non-coding variant.
• BP4: This is not a missense, synonymous or non-coding variant.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PP3: This is not a missense variant.
• PM6: This variant has not been identified de novo.
• PM5: This is not a missense variant.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS4: Only 1 proband with JOAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.