The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000261.2:c.1130C>T

CA1244075

1342202 (ClinVar)

Gene: MYOC (HGNC:4653)
Condition: open-angle glaucoma (MONDO:0005338)
Inheritance Mode: Autosomal dominant inheritance
UUID: c1e7d5a4-2952-462d-95e6-714568dcbcd0
Approved on: 2026-01-19
Published on: 2026-01-21

HGVS expressions

NM_000261.2:c.1130C>T
NC_000001.11:g.171636310G>A
CM000663.2:g.171636310G>A
NC_000001.10:g.171605450G>A
CM000663.1:g.171605450G>A
NC_000001.9:g.169872073G>A
NG_008859.1:g.21324C>T
ENST00000037502.11:c.1130C>T
ENST00000637303.1:c.235-2320G>A
ENST00000638471.1:c.*468C>T
ENST00000037502.10:c.1130C>T
ENST00000614688.1:c.*94C>T
NM_000261.1:c.1130C>T
More

Pathogenic

Met criteria codes 6
PM2_Supporting PS3_Moderate PM5_Supporting PS4 PP1_Strong PP3_Moderate
Not Met criteria codes 8
BA1 PM4 BS3 BS1 PS2 PS1 BP7 BP4

Evidence Links 5

Expert Panel

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.1130C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 377 (p.Thr377Met). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00002668 (2 alleles out of 74,972), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.924, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Thr377Met protein had increased instability levels compared to wild type myocilin protein in these studies (PMIDs: 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3) indicating that this variant did impact protein function. The assays reporting solubility and secretion evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, as the results were conflicting and inconclusive, this evidence was not included. 47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were more family studies published than presented here. 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (≥ 15 probands). There were more probands published than presented here. Another missense variant (c.1130C>A, p.Thr377Lys, Grantham score = 78, ClinVar ID: 2500837) at the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1130C>T, p.Thr377Met variant has a higher Grantham score (= 81) 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_Supporting to apply. In summary, this variant met the criteria to receive a score of 14 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, PM5_Supporting
Met criteria codes
PM2_Supporting
The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00002668 (2 alleles out of 74,972), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles.
PS3_Moderate
The Thr377Met protein had increased instability levels compared to wild type myocilin protein in these studies (PMIDs: 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3) indicating that this variant did impact protein function. The assays reporting solubility and secretion evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, the results were either inconclusive, did not meet the same level of evidence, or were overridden by the stability assays results.

PM5_Supporting
Another missense variant (c.1130C>A, p.Thr377Lys, Grantham score = 78, ClinVar ID: 2500837) at the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1130C>T, p.Thr377Met variant has a higher Grantham score (= 81) 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_Supporting to apply.
PS4
15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (≥ 15 probands). There were more probands published than presented here.
PP1_Strong
47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were more family studies published than presented here.
PP3_Moderate
The REVEL score = 0.924, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function.
Not Met criteria codes
BA1
This criterion was not met as PM2_Supporting has been met.
PM4
This variant does not cause a protein length change.
BS3
This criterion was not met as PS3 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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