Variant: NM_000261.2(MYOC):c.1345G>A (p.Val449Ile)

CA1244035

875033 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 54390ffa-8631-4d0f-8a41-69794f4a5f22

Approved on: 2023-08-08

Published on: 2023-08-08

HGVS expressions

NM_000261.2:c.1345G>A
NM_000261.2(MYOC):c.1345G>A (p.Val449Ile)
NC_000001.11:g.171636095C>T
CM000663.2:g.171636095C>T
NC_000001.10:g.171605235C>T
CM000663.1:g.171605235C>T
NC_000001.9:g.169871858C>T
NG_008859.1:g.21539G>A
ENST00000037502.11:c.1345G>A
ENST00000637303.1:c.235-2535C>T
ENST00000638471.1:c.*683G>A
ENST00000037502.10:c.1345G>A
ENST00000614688.1:c.*309G>A
NM_000261.1:c.1345G>A

Uncertain Significance

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Evidence submitted by expert panel

Glaucoma VCEP

The c.1345G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 449 (p.Val449Ile). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0002940 (9 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 REVEL score = 0.181, 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. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant of the control cohort. Additionally, as PM2_Supporting was not met, 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

• PM5: No other missense variants at this amino acid residue have been identified.
• PM4: This variant does not cause a protein length change.
• 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 South Asian population of gnomAD (v2.1.1) = 0.0002940 (9 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• 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) = 0.0002940 (9 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
• BP7: This is not a synonymous or non-coding variant.
• BP4: The REVEL score = 0.181, 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.
• PS3: No functional evidence has been found for this variant.
• PS4: This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant of the control cohort. Additionally, as PM2_Supporting was not met, PS4 did not apply.
• PP1: No segregations have been reported for this variant.
• PP3: The REVEL score = 0.181, which did not meet the ≥ 0.7 threshold for PP3.