NM_000261.2:c.1463C>T

CA1244017

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 421c87c3-b404-4444-95b5-3613629953ef

Approved on: 2023-07-05

Published on: 2023-07-05

HGVS expressions

NM_000261.2:c.1463C>T
NC_000001.11:g.171635977G>A
CM000663.2:g.171635977G>A
NC_000001.10:g.171605117G>A
CM000663.1:g.171605117G>A
NC_000001.9:g.169871740G>A
NG_008859.1:g.21657C>T
ENST00000037502.11:c.1463C>T
ENST00000637303.1:c.235-2653G>A
ENST00000638471.1:c.*801C>T
ENST00000037502.10:c.1463C>T
ENST00000614688.1:c.*427C>T
NM_000261.1:c.1463C>T

Uncertain Significance

• Met criteria codes: PP3

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

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.1463C>T variant in MYOC is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 488 (p.Ala488Val). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002719 (5 alleles out of 18,386), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.715, 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. 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 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): PP3.

Met criteria codes

• PP3: The REVEL score = 0.715, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

Not Met criteria codes

• BP4: This criterion was not met as PP3 has been met.
• BP7: This is not a synonymous or non-coding variant.
• PM6: This variant has not been identified de novo.
• PM2: The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002719 (5 alleles out of 18,386), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• PM5: No other missense variants at this amino acid residue have been identified.
• PM4: This variant does not cause a protein length change.
• 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.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• PP1: No segregations have been reported for this variant.
• BS3: No functional evidence has been found for this variant.
• BS1: The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002719 (5 alleles out of 18,386), which did not meet the ≥ 0.001 threshold set for BS1.