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.284T>C

CA343718858

1342195 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 753186a8-75c2-4540-9d2e-f07fbdd8fb73

HGVS expressions

NM_000261.2:c.284T>C

NC_000001.11:g.171652328A>G

CM000663.2:g.171652328A>G

NC_000001.10:g.171621468A>G

CM000663.1:g.171621468A>G

NC_000001.9:g.169888091A>G

NG_008859.1:g.5306T>C

ENST00000037502.11:c.284T>C

ENST00000638471.1:c.130+154T>C

ENST00000037502.10:c.284T>C

ENST00000614688.1:c.284T>C

NM_000261.1:c.284T>C

NM_000261.2(MYOC):c.284T>C (p.Leu95Pro)

Uncertain Significance

PM2_Supporting BS3_Supporting

PS4 PS2 PS1 PS3 PP1 PP3 BA1 PM6 BS1 PM5 PM4 BP4 BP7

Evidence Links 1

Expert Panel

Glaucoma VCEP

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.284T>C variant in MYOC is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 95 (p.Leu95Pro). 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 = 0.299, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Leu95Pro 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. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in participants of the control cohorts, thus 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, PM2_Supporting

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.

BS3_Supporting

Applied at the BS3_Moderate level. A previous study (PMID: 16466712) demonstrated that the Leu95Pro 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 L95P protein is secreted at 37°C. This study meets the OddsPath threshold for BS3_Moderate (< 0.23). PubMed:16466712

PS4

The variant has not yet been identified in a proband with POAG or JOAG, only in participants of the control cohorts.

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.

PP1

No segregations have been reported for this variant.

PP3

The REVEL score = 0.299, which did not meet the ≥ 0.7 threshold for PP3.

BA1

This criterion was not met as PM2_Supporting has been met.

PM6

This variant has not been identified de novo.

BS1

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.

BP4

The REVEL score = 0.299, which did not meet the ≤ 0.15 threshold required for BP4.

BP7

This is not a synonymous or non-coding variant.

Approved on: 2022-02-21

Published on: 2022-07-11

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