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(MYOC):c.1297T>C (p.Cys433Arg)

CA119181

7956 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: 17a16a8f-7d35-4be9-9c5a-125f169a53f3

Approved on: 2026-02-05

Published on: 2026-02-04

HGVS expressions

NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)

NM_000261.2:c.1297T>C

NC_000001.11:g.171636143A>G

CM000663.2:g.171636143A>G

NC_000001.10:g.171605283A>G

CM000663.1:g.171605283A>G

NC_000001.9:g.169871906A>G

NG_008859.1:g.21491T>C

ENST00000037502.11:c.1297T>C

ENST00000637303.1:c.235-2487A>G

ENST00000638471.1:c.*635T>C

ENST00000037502.10:c.1297T>C

ENST00000614688.1:c.*261T>C

NM_000261.1:c.1297T>C

Pathogenic

PM2_Supporting PS3_Moderate PS4 PP1_Strong PP3_Moderate

BA1 PM4 PM5 BS3 BS1 PS2 PS1 BP7 BP4

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.1297T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 433 (p.Cys433Arg). 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 = 0.913, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Cys433Arg protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 36267417, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands). In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, 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): PS4, PP1_Strong, PS3_Moderate, PP3_Moderate, 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.

PS3_Moderate

The Cys433Arg protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 36267417, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

The C433R protein has reduced secretion. The assay in this study meets the OddsPath threshold for PS3_Moderate (> 4.3). PubMed:36267417

The C433R protein is unstable. Note: this is a duplicated result from PMID: 23129764 The assay in this study meets the OddsPath threshold for PS3_Moderate (> 4.3) (when combined with PMIDs: 20334347, 21612213, 23129764, 36579626) PubMed:25524706

The C433R 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 C433R 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

PS4

30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands).

PP1_Strong

23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).

PP3_Moderate

The REVEL score = 0.913, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function.

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 (= 180) 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.1298G>A, p.Cys433Tyr, Grantham score = 194).

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.

BP7

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

BP4

This criterion was not met as PP3 has been met.

Curation History

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