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.1412A>G

CA1244027

1342207 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ad15258f-5a19-4150-8c2b-ebf924d30991

HGVS expressions

NM_000261.2:c.1412A>G
NC_000001.11:g.171636028T>C
CM000663.2:g.171636028T>C
NC_000001.10:g.171605168T>C
CM000663.1:g.171605168T>C
NC_000001.9:g.169871791T>C
NG_008859.1:g.21606A>G
ENST00000037502.11:c.1412A>G
ENST00000637303.1:c.235-2602T>C
ENST00000638471.1:c.*750A>G
ENST00000037502.10:c.1412A>G
ENST00000614688.1:c.*376A>G
NM_000261.1:c.1412A>G
NM_000261.2(MYOC):c.1412A>G (p.Tyr471Cys)

Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 14
PS2 PS1 PS3 PS4 PP1 BA1 PM6 PM2 BS3 BS1 PM5 PM4 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.1412A>G variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 471 (p.Tyr471Cys). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0003806 (7 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 = 0.848, 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 Tyr471Cys protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. Although a proband with primary open angle glaucoma had 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 = 0.848, 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.
PS3
Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
The Y471C protein is secreted. This study does not meet the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:27092720
PS4
Although a proband with POAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PP1
No segregations have been reported for this variant.
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) = 0.0003806 (7 alleles out of 18,394), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
BS3
The study reporting functional evidence (PMID: 27092720) demonstrated that the Tyr471Cys protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied.
The Y471C protein is secreted. This study does not meet the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:27092720
BS1
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0003806 (7 alleles out of 18,394), which did not meet the ≥ 0.001 threshold set for BS1.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
Approved on: 2022-02-21
Published on: 2022-07-11
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