Variant: NM_000261.2:c.1504T>C

CA343722794

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: c1e74a9b-b014-42e8-a917-476e4337fb7a

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1504T>C
NC_000001.11:g.171635936A>G
CM000663.2:g.171635936A>G
NC_000001.10:g.171605076A>G
CM000663.1:g.171605076A>G
NC_000001.9:g.169871699A>G
NG_008859.1:g.21698T>C
ENST00000037502.11:c.1504T>C
ENST00000637303.1:c.235-2694A>G
ENST00000638471.1:c.*842T>C
ENST00000037502.10:c.1504T>C
ENST00000614688.1:c.*468T>C
NM_000261.1:c.1504T>C

Uncertain Significance

• Met criteria codes: PS3_Moderate PP1_Moderate PM2_Supporting

• Not Met criteria codes: BA1 BP7 BP4 BS3 BS1 PP3 PM6 PM5 PM4 PS2 PS1 PS4

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.1504T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 502 (p.Ser502Pro). 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 = 0.657, 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 Ser502Pro protein had 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. 6 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PM2_Supporting.

Met criteria codes

• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Ser502Pro protein had 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.
• PP1_Moderate: 6 segregations in 1 family, with JOAG, have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses).
• 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

• BA1: This criterion was not met as PM2_Supporting has been met.
• BP7: This is not a synonymous or non-coding variant.
• BP4: The REVEL score = 0.657, which did not meet the ≤ 0.15 threshold required for BP4.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PP3: The REVEL score = 0.657, 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.
• 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 JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.