Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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CA1244050

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1bd33d32-e082-45c4-bb18-f87fb164c99d

HGVS expressions

NM_000261.2:c.1279G>A
NC_000001.11:g.171636161C>T
CM000663.2:g.171636161C>T
NC_000001.10:g.171605301C>T
CM000663.1:g.171605301C>T
NC_000001.9:g.169871924C>T
NG_008859.1:g.21473G>A
ENST00000037502.11:c.1279G>A
ENST00000637303.1:c.235-2469C>T
ENST00000638471.1:c.*617G>A
ENST00000037502.10:c.1279G>A
ENST00000614688.1:c.*243G>A
NM_000261.1:c.1279G>A

Uncertain Significance

Met criteria codes 2
PP3 BS3_Supporting
Not Met criteria codes 13
PS2 PS1 PS3 PS4 BP4 BP7 BA1 PP1 PM5 PM4 PM6 PM2 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1279G>A variant in MYOC is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 427 (p.Ala427Thr). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.87 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Ala427Thr protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 segregation had been reported for primary open angle glaucoma (POAG), not meeting the ≥ 3 segregations required for PP1 (PMID: 12189160). Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate, PP3
Met criteria codes
PP3
The REVEL score = 0.87, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
BS3_Supporting
A previous study (PMID: 16466712) demonstrated that the Ala427Thr protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function.
The A427T protein is secreted at 37°C. This study meets the OddsPath threshold for BS3_Moderate (< 0.23). PubMed:16466712
Not Met criteria codes
PS2
This variant has not been identified de novo.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS3
This criterion was not met as BS3_Moderate has been met.
PS4
Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
PP1
Only 1 segregation had been reported for primary open angle glaucoma (PMID: 12189160), not meeting the ≥ 3 segregations required for PP1.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
PM2
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
BS1
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
Approved on: 2022-05-10
Published on: 2022-05-25
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