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Variant: NM_000261.2(MYOC):c.1099G>A (p.Gly367Arg)

CA119176

7952 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 75e7b7fd-1db7-4c60-8dd5-07f1be2fa1f2

HGVS expressions

NM_000261.2:c.1099G>A
NM_000261.2(MYOC):c.1099G>A (p.Gly367Arg)
NC_000001.11:g.171636341C>T
CM000663.2:g.171636341C>T
NC_000001.10:g.171605481C>T
CM000663.1:g.171605481C>T
NC_000001.9:g.169872104C>T
NG_008859.1:g.21293G>A
ENST00000037502.11:c.1099G>A
ENST00000637303.1:c.235-2289C>T
ENST00000638471.1:c.*437G>A
ENST00000037502.10:c.1099G>A
ENST00000614688.1:c.*63G>A
NM_000261.1:c.1099G>A

Pathogenic

Met criteria codes 5
PS4 PP1_Strong PM2_Supporting PS3_Moderate PP3
Not Met criteria codes 10
PM5 PM4 PS2 PS1 PM6 BA1 BP7 BP4 BS3 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1099G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 367 (p.Gly367Arg). 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 = 0.787, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Gly367Arg protein had increased insolubility and 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. 35 segregations in 7 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17304254, 32300215, 12189160, 11815346), which fulfilled PP1_Strong (≥7 meioses in >1 family). 16 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32300215, 12189160, 11774072, 9345106, 23453510, 12872267, 14627955, 12442283), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. 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
PS4
16 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32300215, 12189160, 11774072, 9345106, 23453510, 12872267, 14627955, 12442283, 17304254), which met PS4 (≥ 15 probands). There were many more probands published than presented here.
PP1_Strong
35 segregations in 7 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17304254, 32300215, 12189160, 11815346), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were many more families published than presented here.
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.
PS3_Moderate
Previous studies (PMIDs: 16466712. 35196929) demonstrated that the Gly367Arg protein had increased insolubility and 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 = 0.787, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
Not Met criteria codes
PM5
No other missense variants at this amino acid residue have been identified.
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.
PM6
This variant has not been identified de novo.
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.
Approved on: 2022-05-10
Published on: 2022-05-25
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