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

CA1244052

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3c9fd110-a07c-47b2-9a12-8c230ce7cc6c

HGVS expressions

NM_000261.2:c.1265G>A

NC_000001.11:g.171636175C>T

CM000663.2:g.171636175C>T

NC_000001.10:g.171605315C>T

CM000663.1:g.171605315C>T

NC_000001.9:g.169871938C>T

NG_008859.1:g.21459G>A

ENST00000037502.11:c.1265G>A

ENST00000637303.1:c.235-2455C>T

ENST00000638471.1:c.*603G>A

ENST00000037502.10:c.1265G>A

ENST00000614688.1:c.*229G>A

NM_000261.1:c.1265G>A

Uncertain Significance

PP3 BS3_Supporting PM2_Supporting

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

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1265G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 422 (p.Arg422His). The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v2.1.1) = 0.00007961 (2 alleles out of 25,122), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.704, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 10545602) demonstrated that the Arg422His protein had similar solubility 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. Only 1 proband with primary open angle glaucoma had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 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, PP3, PM2_Supporting

PP3

The REVEL score = 0.704, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

BS3_Supporting

Applied at the BS3_Moderate level. A previous study (PMID: 10545602) demonstrated that the Arg422His protein had similar solubility 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.

PM2_Supporting

The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v2.1.1) = 0.00007961 (2 alleles out of 25,122), which met 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

This criterion was not met as BS3_Moderate has been met.

PS4

Only 1 proband with POAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PP1

No segregations have been reported for this variant.

BA1

This criterion was not met as PM2_Supporting has been met.

PM5

PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1264C>T, p.Arg422Cys PMID: 10196380) was not classified as likely pathogenic or pathogenic.

PM4

This variant does not cause a protein length change.

PM6

This variant has not been identified de novo.

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.

Approved on: 2022-05-10

Published on: 2022-05-25

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