Variant: NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)

CA119172

7949 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 399db6af-6807-459a-9953-39c259125cad

Approved on: 2022-03-07

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1102C>T
NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)
NC_000001.11:g.171636338G>A
CM000663.2:g.171636338G>A
NC_000001.10:g.171605478G>A
CM000663.1:g.171605478G>A
NC_000001.9:g.169872101G>A
NG_008859.1:g.21296C>T
ENST00000037502.11:c.1102C>T
ENST00000637303.1:c.235-2292G>A
ENST00000638471.1:c.*440C>T
ENST00000037502.10:c.1102C>T
ENST00000614688.1:c.*66C>T
NM_000261.1:c.1102C>T

Pathogenic

• Met criteria codes: PS3_Moderate PM4 PS4 PP1_Strong

• Not Met criteria codes: BP4 BP7 PM6 PM2 PM5 PS2 PS1 BA1 PP3 BS3 BS1

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.1102C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamine at amino acid 368 (p.Gln368Ter). This variant is predicted to cause a deletion of ≥ 10% of the protein within the conserved olfactomedin domain, meeting PM4. Although this variant had a minor allele frequency of 0.003344 in the European (Finnish) population of gnomAD (84 alleles out of 25,118), which meets the ≥ 0.001 threshold for BS1, Gln368Ter is exempt from this criterion due to its incomplete penetrance and the presence of a common disease haplotype in all carriers. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. This variant is exempt from the rule which normally does not allow the application of PS4 unless PM2_Supporting is met. 23 probands with juvenile or primary open angle glaucoma (JOAG or POAG) have been reported carrying this variant (PMIDs: 11535458, 11004290, 10815160, 22736945, 11803488, 12189160), which met PS4 (≥ 15 probands). As this variant is exempt from the application of BS1, PP1 has been applied. 52 segregations in 10 families, with JOAG or POAG, have been reported (PMIDs: 11004290, 10815160, 11535458), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). There were many more probands and family studies published than presented here. A previous study (PMID: 16466712) demonstrated that the Gln368Ter 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. 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, PM4, PS3_Moderate.

Met criteria codes

• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Gln368Ter 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.
• PM4: This truncating variant is predicted to cause a deletion of ≥ 10% of the protein and is within the conserved olfactomedin domain.
• PS4: This variant is exempt from the rule which normally does not allow the application of PS4 unless PM2_Supporting is met. 23 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 11535458, 11004290, 10815160, 22736945, 11803488, 12189160), which met PS4 (≥15 probands). There were many more probands published than presented here.
• PP1_Strong: As this variant is exempt from the application of BS1, PP1 has been applied. 52 segregations in 10 families, with JOAG or POAG, have been reported (PMIDs: 11004290, 10815160, 11535458), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). There were many more family studies published than presented here.

Not Met criteria codes

• BP4: This is not a missense, synonymous or non-coding variant.
• BP7: This is not a synonymous or non-coding variant.
• PM6: This variant has not been identified de novo.
• PM2: The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v2.1.1) = 0.003344 (84 alleles out of 25,118), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• PM5: This is not a missense variant.
• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• PP3: This is not a missense variant.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: Although this variant had a minor allele frequency of 0.003344 in the European (Finnish) population of gnomAD (84 alleles out of 25,118), which meets the ≥ 0.001 threshold for BS1, Gln368Ter is exempt from this criterion due to its incomplete penetrance and the presence of a common disease haplotype in all carriers.