Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

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

CA343723135

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a3d0ac6f-9515-4a63-baa8-b0ead4e60a8b

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

Likely Pathogenic

PS3_Moderate PP1 PP3 PM2_Supporting PS4_Supporting

BS3 BS1 BP7 BP4 BA1 PS2 PS1 PM4 PM5 PM6

Evidence Links 0

Expert Panel

Glaucoma VCEP

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

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.

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.

PS4_Supporting

2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 12189160), which met PS4_Supporting (≥ 2 probands).

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.

BA1

This criterion was not met as PM2_Supporting 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.

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.

PM6

This variant has not been identified de novo.

Approved on: 2022-05-10

Published on: 2022-05-25

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