The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.


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

CA343724569

1342964 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: b02e5129-d33a-4445-ab99-aa3dd8fc3d6d

HGVS expressions

NM_000261.2:c.1139A>G
NC_000001.11:g.171636301T>C
CM000663.2:g.171636301T>C
NC_000001.10:g.171605441T>C
CM000663.1:g.171605441T>C
NC_000001.9:g.169872064T>C
NG_008859.1:g.21333A>G
ENST00000037502.11:c.1139A>G
ENST00000637303.1:c.235-2329T>C
ENST00000638471.1:c.*477A>G
ENST00000037502.10:c.1139A>G
ENST00000614688.1:c.*103A>G
NM_000261.1:c.1139A>G
NM_000261.2(MYOC):c.1139A>G (p.Asp380Gly)

Uncertain Significance

Met criteria codes 4
PP3 PS3_Moderate PM2_Supporting PM5_Supporting
Not Met criteria codes 11
BP7 BP4 PS2 PS4 PS1 BA1 PP1 PM4 PM6 BS3 BS1

Evidence Links 0

Expert Panel

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.1139A>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glycine at amino acid 380 (p.Asp380Gly). 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 = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Gly 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. Only 1 proband with JOAG (Juvenile open angle glaucoma) had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_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 JOAG by the ClinGen Glaucoma VCEP. The c.1139A>G, p.Asp380Gly variant has a higher Grantham score (= 94) 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 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) 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, PP3, PM2_Supporting, PM5_Supporting.
Met criteria codes
PP3
The REVEL score = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS3_Moderate
A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Gly 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.
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.
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>G, p.Asp380Gly variant has a higher Grantham score (= 94) 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.
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.
PS4
Only 1 proband with JOAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
BA1
This criterion was not met as PM2_Supporting has been met.
PP1
No segregations have been reported for this variant.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
BS3
This criterion was not met as PS3_Moderate has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2022-03-08
Published on: 2022-07-11
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