Evidence Repository
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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  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.

Variant: NM_000261.2:c.736G>A

CA343726300

1342210 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e65830f9-2575-4d92-b8ac-3432db3db1d8
Approved on: 2022-02-21
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.736G>A
NC_000001.11:g.171636704C>T
CM000663.2:g.171636704C>T
NC_000001.10:g.171605844C>T
CM000663.1:g.171605844C>T
NC_000001.9:g.169872467C>T
NG_008859.1:g.20930G>A
ENST00000037502.11:c.736G>A
ENST00000637303.1:c.235-1926C>T
ENST00000638471.1:c.*74G>A
ENST00000037502.10:c.736G>A
ENST00000614688.1:c.736G>A
NM_000261.1:c.736G>A
NM_000261.2(MYOC):c.736G>A (p.Gly246Arg)

Likely Pathogenic

Met criteria codes 4
PP1_Moderate PS3_Moderate PM2_Supporting PP3
Not Met criteria codes 11
BA1 BP7 BP4 BS3 BS1 PM6 PS2 PS1 PS4 PM5 PM4

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.736G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 246 (p.Gly246Arg). 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 = 0.9, which met the ≥0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Gly246Arg 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 open angle glaucoma (JOAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9328473), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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, PP3, PM2_Supporting.
Met criteria codes
PP1_Moderate
6 segregations in 1 family, with JOAG, have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses).
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Gly246Arg 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.
PP3
The REVEL score = 0.9, which met the ≥0.7 threshold for PP3, predicting a damaging effect on MYOC function.
Not Met criteria codes
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.
PM6
This variant has not been identified de novo.
PS2
This variant has not been identified de novo.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS4
Only 1 proband with JOAG had been reported (PMID: 9328473), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
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