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]

Link to SEPIO compliant JSON-LD document

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

CA119186

7961 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PP3 PM2_Supporting PS3_Moderate PP1_Moderate

PS2 PS1 PS4 PM4 PM5 PM6 BA1 BS3 BS1 BP4 BP7

Evidence Links 1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

PDF

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 population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.965, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 35196929) demonstrated that the Asp380His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and 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 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PP3, PM2_Supporting.

PP3

The REVEL score = 0.965, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

PM2_Supporting

This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

PS3_Moderate

A previous study (PMID: 35196929) demonstrated that the Asp380His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and 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. This study meets the OddsPath threshold for PS3_Moderate (> 4.3). PubMed:35196929

PP1_Moderate

9 segregations in 1 family, with 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).

PS2

This variant has not been identified de novo.

PS1

An established pathogenic 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.

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_Supporting) by the ClinGen Glaucoma VCEP (c.1139A>C, p.Asp380Ala, Grantham score=126). This variant was used to apply PM5_Supporting to variants MYOC c.1139A>C, p.Asp380Ala and c.1139A>G, p.Asp380Gly which are located at the same amino acid residue.

PM6

This variant has not been identified de novo.

BA1

This criterion was not met as PM2_Supporting has been met.

BS3

This criterion was not met as PS3_Moderate has been met.

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 a synonymous or non-coding variant.

Approved on: 2022-03-07

Published on: 2022-07-11

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.