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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

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 3
PP1_Moderate PS3_Moderate PM2_Supporting
Not Met criteria codes 12
PS2 PS1 PS4 BP4 BP7 BA1 PP3 PM5 PM4 PM6 BS3 BS1

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.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
PP1_Moderate
6 segregations in 1 family, with JOAG, have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses).
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.
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 JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
BP4
The REVEL score = 0.657, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
BA1
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.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
BS3
This criterion was not met as PS3_Moderate has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2022-05-10
Published on: 2022-05-25
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