Evidence Repository
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
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.

Variant: NM_000261.2:c.1079T>A

CA343724796

1342200 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1de93309-a56d-4676-8add-21b0435de58b

HGVS expressions

NM_000261.2:c.1079T>A
NC_000001.11:g.171636361A>T
CM000663.2:g.171636361A>T
NC_000001.10:g.171605501A>T
CM000663.1:g.171605501A>T
NC_000001.9:g.169872124A>T
NG_008859.1:g.21273T>A
ENST00000037502.11:c.1079T>A
ENST00000637303.1:c.235-2269A>T
ENST00000638471.1:c.*417T>A
ENST00000037502.10:c.1079T>A
ENST00000614688.1:c.*43T>A
NM_000261.1:c.1079T>A
NM_000261.2(MYOC):c.1079T>A (p.Ile360Asn)

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 14
PS2 PS1 PS4 PS3 BA1 PP1 PP3 PM6 PM5 PM4 BS3 BS1 BP4 BP7

Evidence Links 0

Expert Panel

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.1079T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 360 (p.Ile360Asn). 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 = 0.635, 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. The study reporting functional evidence (PMID: 14688426) demonstrated that the Ile360Asn protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. Only 1 proband with primary open angle glaucoma had been reported (PMID: 10980537), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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): 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.
Not Met criteria codes
PS2
This variant has not been identified de novo.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS4
Only 1 proband with POAG had been reported (PMID: 10980537), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS3
The study reporting functional evidence (PMID: 14688426) demonstrated that the Ile360Asn protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.
BA1
This criterion was not met as PM2_Supporting has been met.
PP1
No segregations have been reported for this variant.
PP3
The REVEL score = 0.635, which did not meet the ≥ 0.7 threshold for PP3.
PM6
This variant has not been identified de novo.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
BS3
Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment).
BS1
This criterion was not met as PM2_Supporting has been met.
BP4
The REVEL score = 0.635, 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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