Variant: NM_000261.2:c.1139A>C

CA343724571

1342203 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 9c3b9acb-015c-45ad-956e-7b10bbf078bd

Approved on: 2022-02-21

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1139A>C
NC_000001.11:g.171636301T>G
CM000663.2:g.171636301T>G
NC_000001.10:g.171605441T>G
CM000663.1:g.171605441T>G
NC_000001.9:g.169872064T>G
NG_008859.1:g.21333A>C
ENST00000037502.11:c.1139A>C
ENST00000637303.1:c.235-2329T>G
ENST00000638471.1:c.*477A>C
ENST00000037502.10:c.1139A>C
ENST00000614688.1:c.*103A>C
NM_000261.1:c.1139A>C
NM_000261.2(MYOC):c.1139A>C (p.Asp380Ala)

Pathogenic

• Met criteria codes: PS4_Moderate PP1_Strong PP3 PS3_Moderate PM5_Supporting PM2_Supporting

• Not Met criteria codes: BP7 BP4 PS2 PS1 PM6 PM4 BA1 BS3 BS1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Glaucoma VCEP

The c.1139A>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Alanine at amino acid 380 (p.Asp380Ala). 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 = 0.97, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Asp380Ala protein had 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. 31 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17893668, 9863594, 9832047), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 7 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17893668, 9863594, 9832047), which met PS4_Moderate (≥ 6 probands). Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1139A>C, p.Asp380Ala variant has a higher Grantham score (= 126) 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 11 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting, PM5_Supporting.

Met criteria codes

• PS4_Moderate: 7 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17893668, 9863594, 9832047), which met PS4_Moderate (≥ 6 probands).
• PP1_Strong: 31 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17893668, 9863594, 9832047), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).
• PP3: The REVEL score = 0.97, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Asp380Ala protein had 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.
• PM5_Supporting: Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1139A>C, p.Asp380Ala variant has a higher Grantham score (= 126) 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. This variant would still be classified as pathogenic without the use of PM5_Supporting and was used to apply PM5 to variant MYOC c.1138G>T, p.Asp380Tyr which is located at the same amino acid residue.
• 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.

Not Met criteria codes

• BP7: This is not a synonymous or non-coding variant.
• BP4: This criterion was not met as PP3 has been met.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PM6: This variant has not been identified de novo.
• PM4: This variant does not cause a protein length change.
• 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.