Variant: NM_000261.2(MYOC):c.652G>A (p.Glu218Lys)

CA1244202

875084 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 379e3d8b-135f-41af-9d18-a95bd380893f

Approved on: 2023-06-01

Published on: 2023-06-01

HGVS expressions

NM_000261.2:c.652G>A
NM_000261.2(MYOC):c.652G>A (p.Glu218Lys)
NC_000001.11:g.171638675C>T
CM000663.2:g.171638675C>T
NC_000001.10:g.171607815C>T
CM000663.1:g.171607815C>T
NC_000001.9:g.169874438C>T
NG_008859.1:g.18959G>A
ENST00000037502.11:c.652G>A
ENST00000637303.1:c.280C>T
ENST00000638471.1:c.182G>A
ENST00000037502.10:c.652G>A
ENST00000614688.1:c.652G>A
NM_000261.1:c.652G>A

Uncertain Significance

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.652G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 218 (p.Glu218Lys). The highest allele frequency of this variant (in a population of at least 2,000 alleles) was in the "Other" population of gnomAD (v2.1.1) = 0.0001629 (1 allele out of 6,138) which did not meet the ≥ 0.001 threshold for BS1. The highest allele frequency of this variant (in a population of at least 10,000 alleles) was in the South Asian population of gnomAD (v2.1.1) = 0.0001307 (4 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting. The REVEL score = 0.407, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 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 did not meet any criteria, receiving a score of 0 and a classification 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): none

Not Met criteria codes

• BS3: No functional evidence has been found for this variant.
• BS1: The highest allele frequency of this variant (in a population of at least 2,000 alleles) was in the "Other" population of gnomAD (v2.1.1) = 0.0001629 (1 allele out of 6,138) which did not meet the ≥ 0.001 threshold for BS1.
• BP7: This is not a synonymous or non-coding variant.
• BP4: The REVEL score = 0.407, which did not meet the ≤ 0.15 threshold required for BP4.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• 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: No functional evidence has been found for this variant.
• PS4: Although a proband with POAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP1: Only 1 segregation had been reported for primary open angle glaucoma (PMID: 23922489), not meeting the ≥ 3 segregations required for PP1.
• PP3: The REVEL score = 0.407, which did not meet the ≥ 0.7 threshold for PP3.
• 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 allele frequency of this variant (in a population of at least 10,000 alleles) was in the South Asian population of gnomAD (v2.1.1) = 0.0001307 (4 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.