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.1495A>T

CA343722844

1686792 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: c2449615-dd58-4ce4-be85-4655d3043e9b

Approved on: 2026-01-13

Published on: 2026-01-12

HGVS expressions

NM_000261.2:c.1495A>T

NC_000001.11:g.171635945T>A

CM000663.2:g.171635945T>A

NC_000001.10:g.171605085T>A

CM000663.1:g.171605085T>A

NC_000001.9:g.169871708T>A

NG_008859.1:g.21689A>T

ENST00000037502.11:c.1495A>T

ENST00000637303.1:c.235-2685T>A

ENST00000638471.1:c.*833A>T

ENST00000037502.10:c.1495A>T

ENST00000614688.1:c.*459A>T

NM_000261.1:c.1495A>T

Likely Pathogenic

PS3_Moderate PM2_Supporting PP3 PP1_Moderate PS4_Supporting

BS3 BS1 BP7 BP4 PS2 PS1 BA1 PM4 PM5

Evidence Links 4

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.1495A>T variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 499 (p.Ile499Phe). 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 = 0.67, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Ile499Phe 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. This protein has also been assessed in these other studies (PMIDs: 24333014, 10545602, 16297911), however, the same level of evidence was not met. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 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, PS4_Supporting, PM2_Supporting

PS3_Moderate

The Ile499Phe 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. This protein has also been assessed in these other studies (PMIDs: 24333014, 10545602, 16297911), however, the same level of evidence was not met.

The I499F protein is unstable. The assay in this study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:24333014

The I499F 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

The I499F protein is unstable. Note: this is a duplicated result from PMID: 23129764 PubMed:25524706

The I499F 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

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 = 0.67, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function.

PP1_Moderate

6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses).

PS4_Supporting

2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (≥ 2 probands).

BS3

This criterion was not met as PS3_Moderate has been met.

BS1

This criterion was not met as PM2_Supporting has been met.

BP7

This is not an intronic, synonymous or non-coding variant.

BP4

This criterion was not met as PP3 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.

BA1

This criterion was not met as PM2_Supporting has been met.

PM4

This variant does not cause a protein length change.

PM5

PM5_Supporting could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (= 21) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.1496T>G, p.Ile499Ser, Grantham score = 142).

Curation History

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