Variant: NM_000261.2(MYOC):c.1430T>A (p.Ile477Asn)

CA129023

30205 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 5fe3a673-abb3-4cde-a22c-baa28336fbe7

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1430T>A
NM_000261.2(MYOC):c.1430T>A (p.Ile477Asn)
NC_000001.11:g.171636010A>T
CM000663.2:g.171636010A>T
NC_000001.10:g.171605150A>T
CM000663.1:g.171605150A>T
NC_000001.9:g.169871773A>T
NG_008859.1:g.21624T>A
ENST00000037502.11:c.1430T>A
ENST00000637303.1:c.235-2620A>T
ENST00000638471.1:c.*768T>A
ENST00000037502.10:c.1430T>A
ENST00000614688.1:c.*394T>A
NM_000261.1:c.1430T>A

Likely Pathogenic

• Met criteria codes: PS4_Supporting PM2_Supporting PP1_Strong PS3_Moderate

• Not Met criteria codes: BP7 BP4 BS3 BS1 PP3 PM6 PM5 PM4 PS2 PS1 BA1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1430T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 477 (p.Ile477Asn). 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 = 0.534, 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 Ile477Asn 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. 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), 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_Moderate, PS4_Supporting, PM2_Supporting

Met criteria codes

• PS4_Supporting: 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), 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.
• PP1_Strong: 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family).
• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Ile477Asn 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.

Not Met criteria codes

• BP7: This is not a synonymous or non-coding variant.
• BP4: The REVEL score = 0.534, which did not meet the ≤ 0.15 threshold required for BP4.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PP3: The REVEL score = 0.534, which did not meet the ≥ 0.7 threshold for PP3.
• PM6: This variant has not been identified de novo.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (1430T>G, Ile477Ser,ClinVarID: 7950) was not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• 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.