Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000261.2:c.1504T>C

CA343722794

1686794 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: c1e74a9b-b014-42e8-a917-476e4337fb7a

Approved on: 2026-02-19

Published on: 2026-02-18

HGVS expressions

NM_000261.2:c.1504T>C

NC_000001.11:g.171635936A>G

CM000663.2:g.171635936A>G

NC_000001.10:g.171605076A>G

CM000663.1:g.171605076A>G

NC_000001.9:g.169871699A>G

NG_008859.1:g.21698T>C

ENST00000037502.11:c.1504T>C

ENST00000637303.1:c.235-2694A>G

ENST00000638471.1:c.*842T>C

ENST00000037502.10:c.1504T>C

ENST00000614688.1:c.*468T>C

NM_000261.1:c.1504T>C

Likely Pathogenic

PM2_Supporting PP3 PS3_Moderate PP1_Moderate

BA1 PM5 PM4 BS3 BS1 PS2 PS1 PS4 BP7 BP4

Evidence Links 3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1504T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 502 (p.Ser502Pro). 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 = 0.657, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Ser502Pro protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 6 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, 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): PS3_Moderate, PP1_Moderate, PP3, PM2_Supporting.

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.

PP3

The REVEL score = 0.657, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function.

PS3_Moderate

The Ser502Pro protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

Note: this is a duplicated result from PMID: 23129764 PubMed:25524706

The Ser502Pro protein is unstable. The assay in this study meets the OddsPath threshold for PS3_Moderate (> 4.3) (when combined with PMIDs: 20334347, 23129764, 25524706, 36579626). PubMed:21612213

The Ser502Pro protein is unstable. The assay in this study meets the OddsPath threshold for PS3_Moderate (> 4.3) (when combined with PMIDs: 20334347, 21612213, 25524706, 36579626). PubMed:23129764

PP1_Moderate

6 segregations in 1 family, with JOAG, have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses).

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.

BS3

This criterion was not met as PS3_Moderate has been met.

BS1

This criterion was not met as PM2_Supporting has been met.

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.

PS4

Only 1 proband with JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

BP7

This criterion did not apply to this variant.

BP4

This criterion was not met as PP3 has been met.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.