Variant: NM_000261.2:c.1483G>A

CA343722912

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 04ebf5c1-aacc-4cf5-a48b-1ecc74feb505

HGVS expressions

NM_000261.2:c.1483G>A
NC_000001.11:g.171635957C>T
CM000663.2:g.171635957C>T
NC_000001.10:g.171605097C>T
CM000663.1:g.171605097C>T
NC_000001.9:g.169871720C>T
NG_008859.1:g.21677G>A
ENST00000037502.11:c.1483G>A
ENST00000637303.1:c.235-2673C>T
ENST00000638471.1:c.*821G>A
ENST00000037502.10:c.1483G>A
ENST00000614688.1:c.*447G>A
NM_000261.1:c.1483G>A

Uncertain Significance

• Met criteria codes: BS3_Supporting PM2_Supporting

• Not Met criteria codes: PS2 PS1 PS3 PS4 BA1 PP1 PP3 PM6 PM5 PM4 BS1 BP4 BP7

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1483G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 495 (p.Val495Ile). 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 = 0.424, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 10545602) demonstrated that the Val495Ile 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 -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): BS3_Moderate, PM2_Supporting.

Met criteria codes

• BS3_Supporting: Applied at the BS3_Moderate level. A previous study (PMID: 10545602) demonstrated that the Val495Ile 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: 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

• 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.
• PP3: The REVEL score = 0.424, which did not meet the ≥ 0.7 threshold for PP3.
• PM6: This variant has not been identified de novo.
• PM5: No other missense variants at this amino acid residue have been identified.
• PM4: This variant does not cause a protein length change.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP4: The REVEL score = 0.424, which did not meet the ≤ 0.15 threshold required for BP4.
• BP7: This is not a synonymous or non-coding variant.

Approved on: 2022-05-10

Published on: 2022-05-25