Variant: NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)

CA119170

7947 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 30a3432f-835c-4e0b-942a-7a84d0c5f07c

Approved on: 2022-02-21

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1091G>T
NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)
NC_000001.11:g.171636349C>A
CM000663.2:g.171636349C>A
NC_000001.10:g.171605489C>A
CM000663.1:g.171605489C>A
NC_000001.9:g.169872112C>A
NG_008859.1:g.21285G>T
ENST00000037502.11:c.1091G>T
ENST00000637303.1:c.235-2281C>A
ENST00000638471.1:c.*429G>T
ENST00000037502.10:c.1091G>T
ENST00000614688.1:c.*55G>T
NM_000261.1:c.1091G>T

Likely Pathogenic

• Met criteria codes: PS4_Supporting PP3 PS3_Moderate PM2_Supporting PP1_Strong

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

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.1091G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 364 (p.Gly364Val). 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 = 0.896, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Gly364Val 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. 18 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 9 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, PP3, PS4_Supporting, PM2_Supporting

Met criteria codes

• PS4_Supporting: 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands).
• PP3: The REVEL score = 0.896, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PS3_Moderate: A previous study (PMID: 16466712) demonstrated that the Gly364Val 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.
• 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: 18 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family).

Not Met criteria codes

• 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.
• 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.
• BP7: This is not a synonymous or non-coding variant.
• BP4: This criterion was not met as PP3 has been met.