The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000261.2:c.1495A>T

CA343722844

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: c2449615-dd58-4ce4-be85-4655d3043e9b

HGVS expressions

NM_000261.2:c.1495A>T
NC_000001.11:g.171635945T>A
CM000663.2:g.171635945T>A
NC_000001.10:g.171605085T>A
CM000663.1:g.171605085T>A
NC_000001.9:g.169871708T>A
NG_008859.1:g.21689A>T
ENST00000037502.11:c.1495A>T
ENST00000637303.1:c.235-2685T>A
ENST00000638471.1:c.*833A>T
ENST00000037502.10:c.1495A>T
ENST00000614688.1:c.*459A>T
NM_000261.1:c.1495A>T

Likely Pathogenic

Met criteria codes 4
PP1_Moderate PS3_Moderate PS4_Supporting PM2_Supporting
Not Met criteria codes 11
PS2 PS1 BP4 BP7 BA1 PP3 PM4 PM5 PM6 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1495A>T variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 499 (p.Ile499Phe). 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 = 0.67, 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 Ile499Phe 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. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 6 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): PS3_Moderate, PP1_Moderate, PS4_Supporting, PM2_Supporting
Met criteria codes
PP1_Moderate
6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses).
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Ile499Phe 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.
PS4_Supporting
2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), 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.
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.
BP4
The REVEL score = 0.67, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
BA1
This criterion was not met as PM2_Supporting has been met.
PP3
The REVEL score = 0.67, which did not meet the ≥ 0.7 threshold for PP3.
PM4
This variant does not cause a protein length change.
PM5
This variant was used to apply PM5_Supporting to variant MYOC c.1496T>G p.Ile499Ser (PMID: 11004290) which is located at the same amino acid residue.
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.
Approved on: 2022-05-10
Published on: 2022-05-25
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