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.1298G>A

CA343723939

2500839 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: d06633f1-669c-4aa8-a43d-4f145c930b4e

Approved on: 2026-02-19

Published on: 2026-02-18

HGVS expressions

NM_000261.2:c.1298G>A

NC_000001.11:g.171636142C>T

CM000663.2:g.171636142C>T

NC_000001.10:g.171605282C>T

CM000663.1:g.171605282C>T

NC_000001.9:g.169871905C>T

NG_008859.1:g.21492G>A

ENST00000037502.11:c.1298G>A

ENST00000637303.1:c.235-2488C>T

ENST00000638471.1:c.*636G>A

ENST00000037502.10:c.1298G>A

ENST00000614688.1:c.*262G>A

NM_000261.1:c.1298G>A

Likely Pathogenic

PM2_Supporting PP3_Strong PM5

BS3 BS1 BP4 BP7 PS2 PS3 PS1 PS4 PP1 BA1 PM4

Evidence Links 1

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.1298G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 433 (p.Cys433Tyr). 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 = 0.956, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on MYOC function. The assays in this study (PMID: 40081751), measuring solubility and secretion of the Cys433Tyr protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1). Only 1 proband with juvenile open angle glaucoma (JOAG) had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1297T>C, p.Cys433Arg, Grantham score = 180, ClinVar ID: 7956) in the same codon, has been classified as pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1298G>A, p.Cys433Tyr variant has a higher Grantham score (= 194) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply. 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): PP3_Strong, PM5, PM2_Supporting (PP3 and PM5 capped at 5 points)

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_Strong

The REVEL score = 0.956, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on MYOC function.

PM5

Another missense variant (c.1297T>C, p.Cys433Arg, Grantham score = 180, ClinVar ID: 7956) in the same codon, has been classified as pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1298G>A, p.Cys433Tyr variant has a higher Grantham score (= 194) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply.

BS3

Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment).

The C433Y protein is insoluble in 1 assay and demonstrates reduced secretion and an indeterminate level of solubility in other assays in this study. None of the assays in this study meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:40081751

BS1

This criterion was not met as PM2_Supporting has been met.

BP4

This criterion was not met as PP3 has been met.

BP7

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

PS2

This variant has not been identified de novo.

PS3

The assays in this study (PMID: 40081751), measuring solubility and secretion of the Cys433Tyr protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1).

PS1

An established LP or P variant causing this same amino acid change has not been identified.

PS4

Only 1 proband with juvenile open angle glaucoma (JOAG) had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PP1

No segregations have been reported for this variant.

BA1

This criterion was not met as PM2_Supporting has been met.

PM4

This variant does not cause a protein length change.

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.