NM_000261.2:c.1265G>A

CA1244052

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 3c9fd110-a07c-47b2-9a12-8c230ce7cc6c

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1265G>A
NC_000001.11:g.171636175C>T
CM000663.2:g.171636175C>T
NC_000001.10:g.171605315C>T
CM000663.1:g.171605315C>T
NC_000001.9:g.169871938C>T
NG_008859.1:g.21459G>A
ENST00000037502.11:c.1265G>A
ENST00000637303.1:c.235-2455C>T
ENST00000638471.1:c.*603G>A
ENST00000037502.10:c.1265G>A
ENST00000614688.1:c.*229G>A
NM_000261.1:c.1265G>A

Uncertain Significance

• Met criteria codes: BS3_Supporting PM2_Supporting PP3

• Not Met criteria codes: BS1 BP4 BP7 PS2 PS1 PS3 PS4 BA1 PP1 PM5 PM4 PM6

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1265G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 422 (p.Arg422His). The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v2.1.1) = 0.00007961 (2 alleles out of 25,122), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.704, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 10545602) demonstrated that the Arg422His protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma 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 0 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): BS3_Moderate, PP3, PM2_Supporting

Met criteria codes

• BS3_Supporting: Applied at the BS3_Moderate level. A previous study (PMID: 10545602) demonstrated that the Arg422His protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function.
• PM2_Supporting: The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v2.1.1) = 0.00007961 (2 alleles out of 25,122), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
• PP3: The REVEL score = 0.704, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

Not Met criteria codes

• 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.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS3: This criterion was not met as BS3_Moderate has been met.
• PS4: Only 1 proband with POAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1264C>T, p.Arg422Cys PMID: 10196380) was not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• PM6: This variant has not been identified de novo.