Evidence Repository
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Variant: NM_000261.2(MYOC):c.734G>A (p.Cys245Tyr)

CA119184

7959 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c4135024-f713-41f2-98f8-59f11fd0794d

HGVS expressions

NM_000261.2:c.734G>A
NM_000261.2(MYOC):c.734G>A (p.Cys245Tyr)
NC_000001.11:g.171636706C>T
CM000663.2:g.171636706C>T
NC_000001.10:g.171605846C>T
CM000663.1:g.171605846C>T
NC_000001.9:g.169872469C>T
NG_008859.1:g.20928G>A
ENST00000037502.11:c.734G>A
ENST00000637303.1:c.235-1924C>T
ENST00000638471.1:c.*72G>A
ENST00000037502.10:c.734G>A
ENST00000614688.1:c.734G>A
NM_000261.1:c.734G>A

Uncertain Significance

Met criteria codes 3
PM2_Supporting PP1 PP3
Not Met criteria codes 12
BS3 BS1 BP7 BP4 PS2 PS1 PS4 PS3 PM6 BA1 PM5 PM4

Evidence Links 2

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.734G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 245 (p.Cys245Tyr). 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 = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMIDs: 19234343, 27092720) demonstrated that the Cys245Tyr protein had reduced secretion and solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 16401791), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 16401791), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 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): PM2_Supporting, PP1, PP3
Met criteria codes
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.
PP1
3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 16401791), which fulfilled PP1 (3-4 meioses).
PP3
The REVEL score = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
Not Met criteria codes
BS3
Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment).
The C245Y protein is insoluble. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:19234343
The C245Y protein is not secreted. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:27092720
BS1
This criterion was not met as PM2_Supporting has been met.
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.
PS4
Only 1 proband with JOAG had been reported (PMID: 16401791), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS3
The studies reporting functional evidence (PMIDs: 19234343, 27092720) demonstrated that the Cys245Tyr protein had reduced secretion and solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.
The C245Y protein is insoluble. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:19234343
The C245Y protein is not secreted. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:27092720
PM6
This variant has not been identified de novo.
BA1
This criterion was not met as PM2_Supporting has been met.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
Approved on: 2022-02-21
Published on: 2022-07-11
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