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.1288T>C

CA343724007

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3cbe43ee-e68d-4db2-b1f2-dffdfea3baf6

HGVS expressions

NM_000261.2:c.1288T>C

NC_000001.11:g.171636152A>G

CM000663.2:g.171636152A>G

NC_000001.10:g.171605292A>G

CM000663.1:g.171605292A>G

NC_000001.9:g.169871915A>G

NG_008859.1:g.21482T>C

ENST00000037502.11:c.1288T>C

ENST00000637303.1:c.235-2478A>G

ENST00000638471.1:c.*626T>C

ENST00000037502.10:c.1288T>C

ENST00000614688.1:c.*252T>C

NM_000261.1:c.1288T>C

Uncertain Significance

PP1 PP3 PS4_Supporting PM2_Supporting

PS2 PS1 PS3 BP4 BP7 BA1 PM5 PM4 PM6 BS3 BS1

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1288T>C variant in MYOC is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 430 (p.Phe430Leu). 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 = 0.925, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMID: 17960117) demonstrated that the Phe430Leu 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 2 families, with primary open angle glaucoma (POAG), have been reported (PMID: 17960117), which fulfilled PP1 (3-4 meioses). 2 probands with POAG have been reported carrying this variant (PMID: 17960117), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 4 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): PP1, PP3, PS4_Supporting, PM2_Supporting.

PP1

3 segregations in 2 families, with primary open angle glaucoma (POAG), have been reported (PMID: 17960117), which fulfilled PP1 (3-4 meioses).

PP3

The REVEL score = 0.925, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

PS4_Supporting

2 probands with POAG have been reported carrying this variant (PMID: 17960117), which met PS4_Supporting (≥ 2 probands).

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.

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

The studies reporting functional evidence (PMID: 17960117) demonstrated that the Phe430Leu 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.

BP4

This criterion was not met as PP3 has been met.

BP7

This is not a synonymous or non-coding variant.

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.

PM6

This variant has not been identified de novo.

BS3

No functional evidence has been found for this variant.

BS1

This criterion was not met as PM2_Supporting has been met.

Approved on: 2023-04-04

Published on: 2023-04-04

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.