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.1054G>A

CA1244087

875955 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 73c8b1ac-36e8-4cda-84ac-791bdd290c67

HGVS expressions

NM_000261.2:c.1054G>A
NC_000001.11:g.171636386C>T
CM000663.2:g.171636386C>T
NC_000001.10:g.171605526C>T
CM000663.1:g.171605526C>T
NC_000001.9:g.169872149C>T
NG_008859.1:g.21248G>A
ENST00000037502.11:c.1054G>A
ENST00000637303.1:c.235-2244C>T
ENST00000638471.1:c.*392G>A
ENST00000037502.10:c.1054G>A
ENST00000614688.1:c.*18G>A
NM_000261.1:c.1054G>A
NM_000261.2(MYOC):c.1054G>A (p.Glu352Lys)

Benign

Met criteria codes 2
BA1 BS3_Supporting
Not Met criteria codes 13
PS2 PS1 PS3 PS4 PP1 PP3 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.1054G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 352 (p.Glu352Lys). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the ≥ 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.514, 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. Previous studies (PMIDs: 16466712, 10545602) demonstrated that the Glu352Lys protein had similar solubility and 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. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate
Met criteria codes
BA1
The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the ≥ 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
BS3_Supporting
Applied at the BS3_Moderate level. Previous studies (PMIDs: 16466712, 10545602) demonstrated that the Glu352Lys protein had similar solubility and 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 E352K protein is secreted at 37°C. This study meets the OddsPath threshold for BS3_Moderate (< 0.23). PubMed:16466712
This E352K protein is soluble. This study meets the OddsPath threshold for BS3_Moderate (< 0.23). PubMed:10545602
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.
PS3
This criterion was not met as BS3_Moderate has been met.
PS4
Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PP1
As BA1 was met, PP1 did not apply and segregations were not counted.
PP3
The REVEL score = 0.514, which did not meet the ≥ 0.7 threshold for PP3.
PM6
This variant has not been identified de novo.
PM2
This criterion was not met as BA1 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.
BS1
This criterion was not met as BA1 has been met.
BP4
The REVEL score = 0.514, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
Approved on: 2022-03-06
Published on: 2022-07-11
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