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.1150G>A

CA343724529

1342205 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: 1d496dac-748e-4a00-954f-e320d270d7fa

Approved on: 2025-11-13

Published on: 2025-11-13

HGVS expressions

NM_000261.2:c.1150G>A

NC_000001.11:g.171636290C>T

CM000663.2:g.171636290C>T

NC_000001.10:g.171605430C>T

CM000663.1:g.171605430C>T

NC_000001.9:g.169872053C>T

NG_008859.1:g.21344G>A

ENST00000037502.11:c.1150G>A

ENST00000637303.1:c.235-2340C>T

ENST00000638471.1:c.*488G>A

ENST00000037502.10:c.1150G>A

ENST00000614688.1:c.*114G>A

NM_000261.1:c.1150G>A

Likely Pathogenic

PP3_Moderate PP1_Strong PS4_Supporting PM2_Supporting

BP7 BP4 BS3 BS1 PS2 PS1 PS3 BA1 PM4 PM5

Evidence Links 0

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.1150G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 384 (p.Asp384Asn). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00001667 (1 allele out of 59,992), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.914, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The assay in this study (PMID: 19234343), measuring solubility of the Asp384Asn protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1). 20 segregations in 3 families, with JOAG or POAG, have been reported (PMIDs: 23826516, 19234343, 34273563), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 5 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23826516, 11853639, 19234343, 32476818, 34273563), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 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): PP1_Strong, PP3_Moderate, PS4_Supporting, PM2_Supporting.

PP3_Moderate

The REVEL score = 0.914, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function.

PP1_Strong

20 segregations in 3 families, with JOAG or POAG, have been reported (PMIDs: 23826516, 19234343, 34273563), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).

PS4_Supporting

5 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23826516, 11853639, 19234343, 32476818, 34273563), which met PS4_Supporting (≥ 2 probands).

PM2_Supporting

The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00001667 (1 allele out of 59,992), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles.

BP7

This criterion did not apply to this variant.

BP4

This criterion was not met as PP3 has been met.

BS3

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

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.

PS3

The assay in this study (PMID: 19234343), measuring solubility of the Asp384Asn protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1).

BA1

This criterion was not met as PM2_Supporting has been met.

PM4

This criterion did not apply to this variant.

PM5

PM5 could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (= 23) than the score for the two different missense changes at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.1150G>C, p.Asp384His, Grantham score = 81 and c.1151A>G, p.Asp384Gly, Grantham score = 94).

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.