Variant: NM_000261.2:c.1009C>G

CA343725124

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 27ac9a18-5b54-4405-aa49-e81963645d8a

Approved on: 2023-02-15

Published on: 2023-02-15

HGVS expressions

NM_000261.2:c.1009C>G
NC_000001.11:g.171636431G>C
CM000663.2:g.171636431G>C
NC_000001.10:g.171605571G>C
CM000663.1:g.171605571G>C
NC_000001.9:g.169872194G>C
NG_008859.1:g.21203C>G
ENST00000037502.11:c.1009C>G
ENST00000637303.1:c.235-2199G>C
ENST00000638471.1:c.*347C>G
ENST00000037502.10:c.1009C>G
ENST00000614688.1:c.1009-1C>G
NM_000261.1:c.1009C>G

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: BA1 BP7 BP4 BS3 BS1 PP1 PM6 PM4 PM5 PS2 PS3 PS4 PS1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1009C>G variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Glutamic Acid at amino acid 337 (p.Gln337Glu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.728 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 10916185), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 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, PM2_Supporting

Met criteria codes

• PP3: The REVEL score = 0.728 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PM2_Supporting: This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

Not Met criteria codes

• BA1: This criterion was not met as PM2_Supporting has been met.
• BP7: This is not a synonymous or non-coding variant.
• BP4: This criterion was not met as PP3 has been met.
• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PM6: This variant has not been identified de novo.
• PM4: This variant does not cause a protein length change.
• PM5: PM5_Supporting could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (=29) 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.1010A>G, p.Gln337Arg, Grantham score=43).
• PS2: This variant has not been identified de novo.
• PS3: No functional evidence has been found for this variant.
• PS4: Only 1 proband with POAG had been reported (PMID: 10916185), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.