Variant: NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)

CA119181

7956 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 17a16a8f-7d35-4be9-9c5a-125f169a53f3

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1297T>C
NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)
NC_000001.11:g.171636143A>G
CM000663.2:g.171636143A>G
NC_000001.10:g.171605283A>G
CM000663.1:g.171605283A>G
NC_000001.9:g.169871906A>G
NG_008859.1:g.21491T>C
ENST00000037502.11:c.1297T>C
ENST00000637303.1:c.235-2487A>G
ENST00000638471.1:c.*635T>C
ENST00000037502.10:c.1297T>C
ENST00000614688.1:c.*261T>C
NM_000261.1:c.1297T>C

Pathogenic

• Met criteria codes: PS3_Moderate PP3 PP1_Strong PS4 PM2_Supporting

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1297T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 433 (p.Cys433Arg). 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 = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Cys433Arg 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. 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands). In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting.

Met criteria codes

• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Cys433Arg 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.
• PP3: The REVEL score = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PP1_Strong: 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).
• PS4: 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands).
• 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: This criterion was not met as PP3 has been met.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.
• PM4: This variant does not cause a protein length change.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1298G>A, p.Cys433Tyr, Grantham score = 194, PMID: 33793440) had a higher Grantham score than this variant (Grantham score=180) and was not classified as likely pathogenic or pathogenic. This variant was used to apply PM5_Supporting to variant c.1298G>A, p.Cys433Tyr, PMID: 33793440 which is located at the same amino acid residue.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.