Variant: NM_000261.2:c.1100_1103delinsT

CA1139532761

1342963 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 7e852c02-a0cf-47eb-8f58-3a4248bb9185

Approved on: 2022-03-06

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1100_1103delinsT
NC_000001.11:g.171636337_171636340delinsA
CM000663.2:g.171636337_171636340delinsA
NC_000001.10:g.171605477_171605480delinsA
CM000663.1:g.171605477_171605480delinsA
NC_000001.9:g.169872100_169872103delinsA
NG_008859.1:g.21294_21297delinsT
ENST00000037502.11:c.1100_1103delinsT
ENST00000637303.1:c.235-2293_235-2290delinsA
ENST00000638471.1:c.*438_*441delinsT
ENST00000037502.10:c.1100_1103delinsT
ENST00000614688.1:c.*64_*67delinsT
NM_000261.1:c.1100_1103delinsT
NM_000261.2(MYOC):c.1100_1103delinsT (p.Gly367_Gln368delinsVal)

Likely Pathogenic

• Met criteria codes: PS3_Supporting PS4_Supporting PM2_Supporting PM4_Supporting PP1_Strong

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

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.1100_1103delinsT variant is predicted to cause a change in the length of the myocilin protein due to an in-frame deletion of Gly367 and Gln368 with an insertion of Valine (p.Gly367_Gln368delinsVal). This variant is predicted to cause a deletion of < 10% of the protein within the conserved olfactomedin domain, meeting PM4_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. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. A previous study (PMID: 10545602) demonstrated that the Gly367_Gln368delinsVal protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9639450), which fulfilled PP1_Strong (≥7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9639450), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting

Met criteria codes

• PS3_Supporting: A previous study (PMID: 10545602) demonstrated that the Gly367_Gln368delinsVal protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function.
• PS4_Supporting: 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9639450), which met PS4_Supporting (≥ 2 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.
• PM4_Supporting: This in-frame/truncating variant is predicted to cause a deletion of ≤ 10% of the protein and is within the conserved olfactomedin domain.
• PP1_Strong: 20 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9639450), which fulfilled PP1_Strong (≥7 meioses in >1 family).

Not Met criteria codes

• PM5: This is not a missense variant.
• PM6: This variant has not been identified de novo.
• BS3: This criterion was not met as PS3_Supporting has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP4: This is not a missense, synonymous or non-coding variant.
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP3: This is not a missense variant.