Variant: NM_000261.2:c.1187_1188insCCCAGA

CA1139654950

1342966 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 0915a378-fcdd-444a-be59-bf651850cb53

Approved on: 2022-03-07

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1187_1188insCCCAGA
NC_000001.11:g.171636254_171636255insTGGGTC
CM000663.2:g.171636254_171636255insTGGGTC
NC_000001.10:g.171605394_171605395insTGGGTC
CM000663.1:g.171605394_171605395insTGGGTC
NC_000001.9:g.169872017_169872018insTGGGTC
NG_008859.1:g.21381_21382insCCCAGA
ENST00000037502.11:c.1187_1188insCCCAGA
ENST00000637303.1:c.235-2376_235-2375insTGGGTC
ENST00000638471.1:c.*525_*526insCCCAGA
ENST00000037502.10:c.1187_1188insCCCAGA
ENST00000614688.1:c.*151_*152insCCCAGA
NM_000261.1:c.1187_1188insCCCAGA
NM_000261.2(MYOC):c.1187_1188insCCCAGA (p.Asp395_Glu396insAspPro)

Uncertain Significance

• Met criteria codes: PS3_Moderate PP1 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

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Evidence submitted by expert panel

Glaucoma VCEP

The c.1187_1188insCCCAGA variant in MYOC is predicted to cause a change in the length of the protein due to an in-frame insertion of 2 amino acids (p.Asp395_Glu396insAspPro). 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. A previous study (PMID: 35196929) demonstrated that the Asp395_Glu396insAspPro 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. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 23566828), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 23566828), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 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): PS3_Moderate, PP1, PM2_Supporting, PM4_Supporting.

Met criteria codes

• PS3_Moderate: A previous study (PMID: 35196929) demonstrated that the Asp395_Glu396insAspPro 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: 3 segregations in 1 family, with JOAG, have been reported (PMID: 23566828), which fulfilled PP1 (3-4 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: This variant does not involve an amino acid change.
• PS4: Only 1 proband with JOAG had been reported (PMID: 23566828), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.