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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  • See Evidence submitted by expert panel for details.

Variant: NM_000261.2:c.1442C>T

CA343723135

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: a3d0ac6f-9515-4a63-baa8-b0ead4e60a8b
Approved on: 2022-05-10
Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1442C>T
NC_000001.11:g.171635998G>A
CM000663.2:g.171635998G>A
NC_000001.10:g.171605138G>A
CM000663.1:g.171605138G>A
NC_000001.9:g.169871761G>A
NG_008859.1:g.21636C>T
ENST00000037502.11:c.1442C>T
ENST00000637303.1:c.235-2632G>A
ENST00000638471.1:c.*780C>T
ENST00000037502.10:c.1442C>T
ENST00000614688.1:c.*406C>T
NM_000261.1:c.1442C>T
More

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PS3_Moderate PP1 PP3 PS4_Supporting
Not Met criteria codes 10
BA1 BS3 BS1 BP7 BP4 PS2 PS1 PM6 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1442C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 481 (p.Pro481Leu). 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 = 0.72, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro481Leu 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. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 12189160), which fulfilled PP1 (3-4 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 12189160), which met PS4_Supporting (≥ 2 probands). 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1, PP3, PS4_Supporting, PM2_Supporting
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.
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Pro481Leu 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.
PP1
3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 12189160), which fulfilled PP1 (3-4 meioses).
PP3
The REVEL score = 0.72, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS4_Supporting
2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 12189160), which met PS4_Supporting (≥ 2 probands).
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.
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.
PM5
This likely pathogenic variant was used to apply PM5_Supporting to variant MYOC c.1442C>G, p.Pro481Arg which is located at the same amino acid residue.
Curation History
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