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]
Link to SEPIO compliant JSON-LD document
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.

Variant: NM_000261.2:c.473G>A

CA1244272

874204 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5d3129ae-6562-46a8-a69f-57f2a16a79cd

HGVS expressions

NM_000261.2:c.473G>A
NC_000001.11:g.171652139C>T
CM000663.2:g.171652139C>T
NC_000001.10:g.171621279C>T
CM000663.1:g.171621279C>T
NC_000001.9:g.169887902C>T
NG_008859.1:g.5495G>A
ENST00000037502.11:c.473G>A
ENST00000638471.1:c.130+343G>A
ENST00000037502.10:c.473G>A
ENST00000614688.1:c.473G>A
NM_000261.1:c.473G>A
NM_000261.2(MYOC):c.473G>A (p.Arg158Gln)

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 1
BS3_Supporting
Not Met criteria codes 14
PS2 PS1 PS4 PS3 PP1 PP3 BA1 PM6 PM2 PM5 PM4 BS1 BP4 BP7

Evidence Links 2

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.473G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 158 (p.Arg158Gln). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175, (4 alleles out of 18,394), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.52, 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 Arg158Gln protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate
Met criteria codes
BS3_Supporting
Applied at the BS3_Moderate level. A previous study (PMID: 16466712) demonstrated that the Arg158Gln protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function.
The R158Q protein is secreted at 37°C. This study meets the OddsPath threshold for BS3_Moderate (< 0.23). PubMed:16466712
The R158Q protein is secreted This study does not meet the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:14688426
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.
PS4
Although multiple probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PS3
This criterion was not met as BS3_Moderate has been met.
PP1
No segregations have been reported for this variant.
PP3
The REVEL score = 0.52, which did not meet the ≥ 0.7 threshold for PP3.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
PM6
This variant has not been identified de novo.
PM2
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175, (4 alleles out of 18,394), which does not meet the ≤0.0001 threshold set for this criterion.
PM5
PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.473G>T, p.Arg158Leu PMID: 33793440) was not classified as likely pathogenic or pathogenic.
PM4
This variant does not cause a protein length change.
BS1
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175, (4 alleles out of 18,394), which does not meet the ≥ 0.001 threshold set for BS1 nor the threshold for alleles identified (≥5).
BP4
The REVEL score = 0.52, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
Approved on: 2022-02-21
Published on: 2022-07-11
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.