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.1138G>T

CA343724573

1342965 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 63fa2457-cd6f-4e00-8e40-a98b6cd33387
Approved on: 2022-03-08
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1138G>T
NC_000001.11:g.171636302C>A
CM000663.2:g.171636302C>A
NC_000001.10:g.171605442C>A
CM000663.1:g.171605442C>A
NC_000001.9:g.169872065C>A
NG_008859.1:g.21332G>T
ENST00000037502.11:c.1138G>T
ENST00000637303.1:c.235-2328C>A
ENST00000638471.1:c.*476G>T
ENST00000037502.10:c.1138G>T
ENST00000614688.1:c.*102G>T
NM_000261.1:c.1138G>T
NM_000261.2(MYOC):c.1138G>T (p.Asp380Tyr)
More

Likely Pathogenic

Met criteria codes 4
PS3_Moderate PM2_Supporting PP3 PM5
Not Met criteria codes 11
BA1 BS3 BS1 BP4 BP7 PS2 PS4 PS1 PP1 PM4 PM6

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.1138G>T variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Tyrosine at amino acid 380 (p.Asp380Tyr). 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 Asp380Tyr 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 primary open angle glaucoma had been reported (PMID: 31302906), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1139A>C, p.Asp380Ala, Grantham score = 126, PMID: 9832047) in the same codon has been classified as pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1138G>T, p.Asp380Tyr variant has a higher Grantham score (= 160) 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 to apply. 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM5, PS3_Moderate, PP3, PM2_Supporting.
Met criteria codes
PS3_Moderate
A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Tyr 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.
PP3
The REVEL score = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PM5
Another missense variant (c.1139A>C, p.Asp380Ala, Grantham score = 126, PMID: 9832047) in the same codon has been classified as pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1138G>T, p.Asp380Tyr variant has a higher Grantham score (= 160) 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 to apply.
Not Met criteria codes
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.
PS2
This variant has not been identified de novo.
PS4
Only 1 proband with POAG had been reported (PMID: 31302906), 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.
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.
Curation History
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