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.898G>A

CA1244125

1342968 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 745dd529-1307-494f-9309-d0bf0131afb9

HGVS expressions

NM_000261.2:c.898G>A
NC_000001.11:g.171636542C>T
CM000663.2:g.171636542C>T
NC_000001.10:g.171605682C>T
CM000663.1:g.171605682C>T
NC_000001.9:g.169872305C>T
NG_008859.1:g.21092G>A
ENST00000037502.11:c.898G>A
ENST00000637303.1:c.235-2088C>T
ENST00000638471.1:c.*236G>A
ENST00000037502.10:c.898G>A
ENST00000614688.1:c.898G>A
NM_000261.1:c.898G>A
NM_000261.2(MYOC):c.898G>A (p.Glu300Lys)

Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 14
PS2 PS1 PS4 PS3 PP1 PM5 PM4 PM6 PM2 BA1 BS3 BS1 BP4 BP7

Evidence Links 1

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.898G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 300 (p.Glu300Lys). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0005018 (10 alleles out of 19 928), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.734 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 27092720) demonstrated that the Glu300Lys protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. 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 met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3
Met criteria codes
PP3
The REVEL score = 0.734 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
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 probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PS3
The study reporting functional evidence (PMID: 27092720) demonstrated that the Glu300Lys protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.
The E300K protein is not secreted. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:27092720
PP1
No segregations have been reported for this variant.
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.
PM2
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0005018, (10 alleles out of 19 928), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
BS3
Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment).
The E300K protein is not secreted. This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). PubMed:27092720
BS1
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0005018, (10 alleles out of 19 928), which did not meet the ≥ 0.001 threshold set for BS1.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
Approved on: 2022-03-06
Published on: 2022-07-11
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