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

Variant: NM_000261.2:c.761C>T

CA343726245

1342967 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8d13c39d-90c0-4a37-af54-854d4349e596
Approved on: 2022-03-06
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.761C>T
NC_000001.11:g.171636679G>A
CM000663.2:g.171636679G>A
NC_000001.10:g.171605819G>A
CM000663.1:g.171605819G>A
NC_000001.9:g.169872442G>A
NG_008859.1:g.20955C>T
ENST00000037502.11:c.761C>T
ENST00000637303.1:c.235-1951G>A
ENST00000638471.1:c.*99C>T
ENST00000037502.10:c.761C>T
ENST00000614688.1:c.761C>T
NM_000261.1:c.761C>T
NM_000261.2(MYOC):c.761C>T (p.Pro254Leu)

Likely Pathogenic

Met criteria codes 4
PS2_Moderate PP3 PS3_Moderate PM2_Supporting
Not Met criteria codes 11
BS3 BS1 PS4 PS1 BP7 BP4 BA1 PP1 PM4 PM5 PM6

Evidence Links 1

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.761C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 254 (p.Pro254Leu).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. A previous study (PMID: 35196929) demonstrated that the Pro254Leu protein had increased insolubility and 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. A confirmed de novo proband with juvenile open angle glaucoma was identified (PMID: 27080696), meeting PS2_Moderate. However, as this was the only proband identified, the ≥ 2 probands threshold required to meet PS4_Supporting was not met. 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): PS2_Moderate, PS3_Moderate, PP3, PM2_Supporting
Met criteria codes
PS2_Moderate
1 confirmed de novo proband with JOAG has been identified.
PP3
The REVEL score = 0.925, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS3_Moderate
A previous study (PMID: 35196929) demonstrated that the Pro254Leu protein had increased insolubility and 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.
The P254L protein is not secreted and insoluble. This study meets the OddsPath threshold for PS3_Moderate (> 4.3). PubMed:35196929
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
BS3
This criterion was not met as PS3_Moderate has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
PS4
Only 1 proband with JOAG had been reported (PMID: 27080696), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
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.
PP1
No segregations have been reported for this variant.
PM4
This variant does not cause a protein length change.
PM5
This variant was used to apply PM5_Supporting to variant MYOC c.761C>G, p.Pro254Arg, which is located at the same amino acid residue. Another variant at the same amino acid residue, c.760C>A, p.Pro254Thr, could not be used to apply PM5 as it was not classified as likely pathogenic or pathogenic.
PM6
This criterion was not met as PS2 has been met.
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