Variant: NM_000261.2(MYOC):c.865G>A (p.Asp289Asn)

CA1244135

293713 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 75f6b14a-c029-4bab-832f-d4ca487a030a

HGVS expressions

NM_000261.2:c.865G>A
NM_000261.2(MYOC):c.865G>A (p.Asp289Asn)
NC_000001.11:g.171636575C>T
CM000663.2:g.171636575C>T
NC_000001.10:g.171605715C>T
CM000663.1:g.171605715C>T
NC_000001.9:g.169872338C>T
NG_008859.1:g.21059G>A
ENST00000037502.11:c.865G>A
ENST00000637303.1:c.235-2055C>T
ENST00000638471.1:c.*203G>A
ENST00000037502.10:c.865G>A
ENST00000614688.1:c.865G>A
NM_000261.1:c.865G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

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

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.865G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic Acid by Asparagine at amino acid 289 (p.Asp289Asn). The highest minor 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) = 0.00003296 (1 allele out of 30,342), which met the ≤ 0.0001 threshold set for PM2_Supporting. The REVEL score = 0.428, 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 was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma, thus PS4 did not apply. 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 , in a population of at least 10,000 alleles, was in the South Asian population of gnomAD (v2.1.1) = 0.00003296 (1 allele out of 30,342), which met the ≤ 0.0001 threshold set for PM2_Supporting.

Not Met criteria codes

• PS4: This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma.
• 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.
• PP1: No segregations have been reported for this variant.
• PP3: The REVEL score = 0.428, 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.
• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP4: The REVEL score = 0.428, which did not meet the ≤ 0.15 threshold required for BP4.
• BP7: This is not a synonymous or non-coding variant.

Approved on: 2023-08-08

Published on: 2023-08-08