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

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
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: 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).
Not Met criteria codes
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.
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.
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.
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.
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