Variant: NM_000261.2:c.1121G>T

CA343724639

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 0e4ca6b6-e46a-473e-8714-7c8602e45f45

Approved on: 2023-04-04

Published on: 2023-04-04

HGVS expressions

NM_000261.2:c.1121G>T
NC_000001.11:g.171636319C>A
CM000663.2:g.171636319C>A
NC_000001.10:g.171605459C>A
CM000663.1:g.171605459C>A
NC_000001.9:g.169872082C>A
NG_008859.1:g.21315G>T
ENST00000037502.11:c.1121G>T
ENST00000637303.1:c.235-2311C>A
ENST00000638471.1:c.*459G>T
ENST00000037502.10:c.1121G>T
ENST00000614688.1:c.*85G>T
NM_000261.1:c.1121G>T

Uncertain Significance

• Met criteria codes: PS4_Supporting PP3 PM2_Supporting

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

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.1121G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 374 (p.Gly374Val). 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 = 0.904, 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. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID: 21552496), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 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, PS4_Supporting, PM2_Supporting.

Met criteria codes

• PS4_Supporting: 2 probands with POAG have been reported carrying this variant (PMID: 21552496), which met PS4_Supporting (≥ 2 probands).
• PP3: The REVEL score = 0.904, 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.
• 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.