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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  • See Evidence submitted by expert panel for details.

CA1244022

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: bf05c3e4-02c8-4fe4-83d8-8fbebe319aba
Approved on: 2022-05-10
Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1441C>T
NC_000001.11:g.171635999G>A
CM000663.2:g.171635999G>A
NC_000001.10:g.171605139G>A
CM000663.1:g.171605139G>A
NC_000001.9:g.169871762G>A
NG_008859.1:g.21635C>T
ENST00000037502.11:c.1441C>T
ENST00000637303.1:c.235-2631G>A
ENST00000638471.1:c.*779C>T
ENST00000037502.10:c.1441C>T
ENST00000614688.1:c.*405C>T
NM_000261.1:c.1441C>T

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 14
BP7 BP4 PS2 PS1 PS4 PS3 PP1 PP3 PM4 PM5 PM6 BA1 BS3 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1441C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Serine at amino acid 481 (p.Pro481Ser). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.00005438 (1 allele out of 18,388), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.684, 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: 35196929) demonstrated conflicting results for the Pro481Ser protein, therefore, PS3 or BS3 was not applied. Only 1 proband with primary open angle glaucoma had been reported (PMID: 15534471), 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM2_Supporting
Met criteria codes
PM2_Supporting
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.00005438 (1 allele out of 18,388), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
Not Met criteria codes
BP7
This is not a synonymous or non-coding variant.
BP4
The REVEL score = 0.684, which did not meet the ≤ 0.15 threshold required for BP4.
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
Only 1 proband with POAG had been reported (PMID: 15534471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PS3
A previous study (PMID: 35196929) demonstrated conflicting results for the Pro481Ser protein, thus PS3 was not applied.
The P481S protein demonstrated the conflicting results of being secreted but insoluble. PubMed:35196929
PP1
No segregations have been reported for this variant.
PP3
The REVEL score = 0.684, which did not meet the ≥ 0.7 threshold for PP3.
PM4
This variant does not cause a protein length change.
PM5
PM5_Supporting could not be applied to this novel missense variant as it did not meet PP3 and the Grantham score was lower (= 74) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.1442C>T, p.Pro481Leu, Grantham score = 98, PMID:10196380).
PM6
This variant has not been identified de novo.
BA1
This criterion was not met as PM2_Supporting has been met.
BS3
A previous study (PMID: 35196929) demonstrated conflicting results for the Pro481Ser protein, thus BS3 was not applied.
The P481S protein demonstrated the conflicting results of being secreted but insoluble. PubMed:35196929
BS1
This criterion was not met as PM2_Supporting has been met.
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