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

CA343726245

1342967 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

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: PM2_Supporting PS3_Moderate PP3 PS2_Moderate

• Not Met criteria codes: BS3 BS1 BP7 BP4 PS4 PS1 PM4 PM5 BA1 PM6 PP1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

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

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

• 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.
• 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.
• PP3: The REVEL score = 0.925, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PS2_Moderate: 1 confirmed de novo proband with JOAG has been identified.

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.
• BP7: This is not a synonymous or non-coding variant.
• BP4: This criterion was not met as PP3 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.
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM6: This criterion was not met as PS2 has been met.
• PP1: No segregations have been reported for this variant.