Variant: NM_000261.2:c.1139A>G

CA343724569

1342964 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: b02e5129-d33a-4445-ab99-aa3dd8fc3d6d

HGVS expressions

NM_000261.2:c.1139A>G
NC_000001.11:g.171636301T>C
CM000663.2:g.171636301T>C
NC_000001.10:g.171605441T>C
CM000663.1:g.171605441T>C
NC_000001.9:g.169872064T>C
NG_008859.1:g.21333A>G
ENST00000037502.11:c.1139A>G
ENST00000637303.1:c.235-2329T>C
ENST00000638471.1:c.*477A>G
ENST00000037502.10:c.1139A>G
ENST00000614688.1:c.*103A>G
NM_000261.1:c.1139A>G
NM_000261.2(MYOC):c.1139A>G (p.Asp380Gly)

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PS3_Moderate PM5_Supporting

• Not Met criteria codes: PS2 PS4 PS1 BA1 PP1 PM6 PM4 BS3 BS1 BP4 BP7

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.1139A>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glycine at amino acid 380 (p.Asp380Gly). 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. The REVEL score = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Gly 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. Only 1 proband with JOAG (Juvenile open angle glaucoma) had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1139A>G, p.Asp380Gly variant has a higher Grantham score (= 94) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. 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, PP3, PM2_Supporting, PM5_Supporting.

Met criteria codes

• PP3: The REVEL score = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• 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.
• PS3_Moderate: A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Gly 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.
• PM5_Supporting: Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1139A>G, p.Asp380Gly variant has a higher Grantham score (= 94) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply.

Not Met criteria codes

• PS2: This variant has not been identified de novo.
• PS4: Only 1 proband with JOAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PM6: This variant has not been identified de novo.
• PM4: This variant does not cause a protein length change.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP4: This criterion was not met as PP3 has been met.
• BP7: This is not a synonymous or non-coding variant.

Approved on: 2022-03-08

Published on: 2022-07-11