Variant: NM_000261.2:c.1058C>T

CA1244086

1013538 (ClinVar)

Gene: MYOC

Condition: open-angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: d41b1c25-85d2-44e3-b208-881563323147

Approved on: 2025-12-04

Published on: 2025-12-04

HGVS expressions

NM_000261.2:c.1058C>T
NC_000001.11:g.171636382G>A
CM000663.2:g.171636382G>A
NC_000001.10:g.171605522G>A
CM000663.1:g.171605522G>A
NC_000001.9:g.169872145G>A
NG_008859.1:g.21252C>T
ENST00000037502.11:c.1058C>T
ENST00000637303.1:c.235-2248G>A
ENST00000638471.1:c.*396C>T
ENST00000037502.10:c.1058C>T
ENST00000614688.1:c.*22C>T
NM_000261.1:c.1058C>T

Likely Benign

• Met criteria codes: BS3_Supporting BS1

• Not Met criteria codes: BP7 BP4 PS2 PS1 PS3 PS4 PP3 PP1 BA1 PM5 PM4 PM2

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.1058C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 353 (p.Thr353Ile). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.005259, which met the ≥ 0.001 threshold set for BS1 (236 alleles out of 44,876, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.316, 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 Thr353Ile protein had similar stability and secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 25524706). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This protein has also been assessed in this other study (PMID: 36579626), however, the same level of evidence was not met. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BS3_Moderate.

Met criteria codes

• BS3_Supporting: applied at BS3_Moderate level: The Thr353Ile protein had similar stability and secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 25524706). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This protein has also been assessed in this other study (PMID: 36579626), however, the same level of evidence was not met.
• BS1: The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.005259, which met the ≥ 0.001 threshold set for BS1 (236 alleles out of 44,876, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).

Not Met criteria codes

• BP7: This criterion did not apply to this variant.
• BP4: The REVEL score = 0.316, which did not meet the ≤ 0.290 threshold required for BP4.
• 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.
• PS4: Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP3: The REVEL score = 0.316, which did not meet the ≥ 0.644 threshold required for PP3.
• PP1: As BS1 was met, PP1 did not apply and segregations were not counted.
• BA1: This criterion was not met as BS1 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.
• PM2: This criterion was not met as BS1 has been met.