Variant: NM_000261.2:c.284T>C

CA343718858

1342195 (ClinVar)

Gene: MYOC

Condition: open-angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 753186a8-75c2-4540-9d2e-f07fbdd8fb73

Approved on: 2025-12-04

Published on: 2025-12-04

HGVS expressions

NM_000261.2:c.284T>C
NC_000001.11:g.171652328A>G
CM000663.2:g.171652328A>G
NC_000001.10:g.171621468A>G
CM000663.1:g.171621468A>G
NC_000001.9:g.169888091A>G
NG_008859.1:g.5306T>C
ENST00000037502.11:c.284T>C
ENST00000638471.1:c.130+154T>C
ENST00000037502.10:c.284T>C
ENST00000614688.1:c.284T>C
NM_000261.1:c.284T>C

Uncertain Significance

• Met criteria codes: BS3_Supporting PM2_Supporting

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.0.0

Evidence submitted by expert panel

Glaucoma VCEP

The c.284T>C variant in MYOC is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 95 (p.Leu95Pro). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.299, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Leu95Pro protein had similar secretion levels to wild type myocilin protein in this study (PMID: 16466712). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in participants of the control cohorts, thus PS4 did not apply. 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, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS3_Moderate, PM2_Supporting.

Met criteria codes

• BS3_Supporting: applied at BS3_Moderate level: The Leu95Pro protein had similar secretion levels to wild type myocilin protein in this study (PMID: 16466712). The assay 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 genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles.

Not Met criteria codes

• PS4: The variant has not yet been identified in a proband with POAG or JOAG, only in participants of the control cohorts.
• PS2: This variant has not been identified de novo.
• PS1: An established LP or P variant causing this same amino acid change has not been identified.
• PS3: This criterion was not met as BS3_Moderate has been met.
• PP1: No segregations have been reported for this variant.
• PP3: This missense variant had a REVEL score = 0.299, which did not meet the ≥ 0.644 threshold required for PP3.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM5: No other LP or P missense variants at this amino acid residue have been identified.
• PM4: This criterion did not apply to this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP7: This criterion did not apply to this variant.
• BP4: This missense variant had a REVEL score = 0.299, which did not meet the ≤ 0.290 threshold required for BP4.