Variant: NM_000261.2:c.767C>T

CA1244159

1684936 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 7aade9cf-c2bd-4f71-bc0c-964c6aa7a669

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000261.2:c.767C>T
NC_000001.11:g.171636673G>A
CM000663.2:g.171636673G>A
NC_000001.10:g.171605813G>A
CM000663.1:g.171605813G>A
NC_000001.9:g.169872436G>A
NG_008859.1:g.20961C>T
ENST00000037502.11:c.767C>T
ENST00000637303.1:c.235-1957G>A
ENST00000638471.1:c.*105C>T
ENST00000037502.10:c.767C>T
ENST00000614688.1:c.767C>T
NM_000261.1:c.767C>T
NM_000261.2(MYOC):c.767C>T (p.Thr256Met)

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

• 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.767C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 256 (p.Thr256Met). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001555 (20 alleles out of 128,606), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.664, 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 probands with juvenile or primary open angle glaucoma have 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

• 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 European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001555 (20 alleles out of 128,606), 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 European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001555 (20 alleles out of 128,606), 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 = 0.664, 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: Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP1: No segregations have been reported for this variant.
• PP3: The REVEL score = 0.664, which did not meet the ≥ 0.7 threshold for PP3.