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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CA1244048

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2b6ac23d-3cec-4245-8579-f483c947997f

HGVS expressions

NM_000261.2:c.1290C>T
NC_000001.11:g.171636150G>A
CM000663.2:g.171636150G>A
NC_000001.10:g.171605290G>A
CM000663.1:g.171605290G>A
NC_000001.9:g.169871913G>A
NG_008859.1:g.21484C>T
ENST00000037502.11:c.1290C>T
ENST00000637303.1:c.235-2480G>A
ENST00000638471.1:c.*628C>T
ENST00000037502.10:c.1290C>T
ENST00000614688.1:c.*254C>T
NM_000261.1:c.1290C>T

Uncertain Significance

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

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1290C>T variant in MYOC is a synonymous variant (p.Phe430=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The CADD score (v1.6) = 6.961, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 2.25 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4.
Met criteria codes
BP4
The CADD score (v1.6) = 6.961, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
Not Met criteria codes
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
PS4
Only 1 proband with JOAG had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS2
This variant has not been identified de novo.
PS1
This variant does not involve an amino acid change.
PS3
No functional evidence has been found for this variant.
PP1
No segregations have been reported for this variant.
PP3
This is not a missense variant.
PM6
This variant has not been identified de novo.
PM2
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
PM5
This is not a missense variant.
PM4
This variant does not cause a protein length change.
BS3
No functional evidence has been found for this variant.
BS1
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
BP7
Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 2.25 (threshold < 0), indicating conservation at this site.
Approved on: 2023-02-15
Published on: 2023-02-15
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