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.1138G>C (p.Asp380His)

CA119186

7961 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: b4a3436c-9253-4e58-a843-cc3eb040d0d0

Approved on: 2025-12-04

Published on: 2025-12-04

HGVS expressions

NM_000261.2:c.1138G>C

NM_000261.2(MYOC):c.1138G>C (p.Asp380His)

NC_000001.11:g.171636302C>G

CM000663.2:g.171636302C>G

NC_000001.10:g.171605442C>G

CM000663.1:g.171605442C>G

NC_000001.9:g.169872065C>G

NG_008859.1:g.21332G>C

ENST00000037502.11:c.1138G>C

ENST00000637303.1:c.235-2328C>G

ENST00000638471.1:c.*476G>C

ENST00000037502.10:c.1138G>C

ENST00000614688.1:c.*102G>C

NM_000261.1:c.1138G>C

Likely Pathogenic

PM2_Supporting PS3_Moderate PP3_Strong PP1_Moderate

BA1 PM4 PM5 BS3 BS1 PS2 PS1 PS4 BP7 BP4

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.1138G>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic Acid by Histidine at amino acid 380 (p.Asp380His). 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 = 0.965, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on MYOC function. The Asp380His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein in this study (PMID: 35196929). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 17499207), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 17499207), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 9 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, PS3_Moderate, PP1_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 Asp380His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein in this study (PMID: 35196929). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

The D380H protein is not secreted and insoluble. The assay in this study meets the OddsPath threshold for PS3_Moderate (> 4.3). PubMed:35196929

PP3_Strong

The REVEL score = 0.965, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on MYOC function.

PP1_Moderate

9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 17499207), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion).

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 variant as the other missense variant with a lower Grantham score at the same amino acid residue (c.1138G>A, p.Asp380Asn, PMID: 12362081) was not classified as likely pathogenic or pathogenic and although it did meet PP3, the Grantham score was lower (= 81) than the score for the different missense change at the same amino acid residue determined to be pathogenic (without the application of PM5) by the ClinGen Glaucoma VCEP (c.1139A>C, p.Asp380Ala, Grantham score=126). This variant was used to apply PM5 to variants MYOC c.1139A>C, p.Asp380Ala and c.1139A>G, p.Asp380Gly which are located at the same amino acid residue.

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.

PS4

Only 1 proband with JOAG had been reported (PMID: 17499207), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

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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