The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.


Variant: NM_000261.2:c.1087G>A

CA343724770

1342962 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: f9eac996-1b82-4222-b685-e17c4c244c3d

HGVS expressions

NM_000261.2:c.1087G>A
NC_000001.11:g.171636353C>T
CM000663.2:g.171636353C>T
NC_000001.10:g.171605493C>T
CM000663.1:g.171605493C>T
NC_000001.9:g.169872116C>T
NG_008859.1:g.21281G>A
ENST00000037502.11:c.1087G>A
ENST00000637303.1:c.235-2277C>T
ENST00000638471.1:c.*425G>A
ENST00000037502.10:c.1087G>A
ENST00000614688.1:c.*51G>A
NM_000261.1:c.1087G>A
NM_000261.2(MYOC):c.1087G>A (p.Ala363Thr)

Likely Pathogenic

Met criteria codes 5
PP1_Moderate PP3 PS4_Supporting PS3_Moderate PM2_Supporting
Not Met criteria codes 10
PS2 PS1 BP4 BP7 BA1 PM5 PM4 PM6 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1087G>A variant in MYOC is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 363 (p.Ala363Thr). 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 = 0.905, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Ala363Thr 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. 5 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 18334962, 16491872), which fulfilled PP1_Moderate (5-6 meioses). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 15534471, 18334962), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 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, PP3, PS4_Supporting, PM2_Supporting.
Met criteria codes
PP1_Moderate
5 segregations in 3 families, with JOAG or POAG, have been reported (PMIDs: 18334962, 16491872), which fulfilled PP1_Moderate (5-6 meioses).
PP3
The REVEL score = 0.905, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS4_Supporting
4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 15534471, 18334962), which met PS4_Supporting (≥ 2 probands).
PS3_Moderate
A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Ala363Thr 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.
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
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
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.
Approved on: 2022-03-08
Published on: 2022-07-11
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