Variant: NM_000261.2:c.14G>A

CA343720209

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 44e6d4ec-6733-4fe2-a78e-1ca1a3bf2a51

HGVS expressions

NM_000261.2:c.14G>A
NC_000001.11:g.171652598C>T
CM000663.2:g.171652598C>T
NC_000001.10:g.171621738C>T
CM000663.1:g.171621738C>T
NC_000001.9:g.169888361C>T
NG_008859.1:g.5036G>A
ENST00000037502.11:c.14G>A
ENST00000638471.1:c.14G>A
ENST00000037502.10:c.14G>A
ENST00000614688.1:c.14G>A
NM_000261.1:c.14G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting BP4

• Not Met criteria codes: PM6 PM5 PM4 BS3 BS1 BP7 PS4 PS2 PS1 PS3 BA1 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.14G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 5 (p.Cys5Tyr). 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 = 0.044, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 32476818), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 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): BP4, PM2_Supporting.

Met criteria codes

• 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.
• BP4: The REVEL score = 0.044, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function.

Not Met criteria codes

• PM6: This variant has not been identified de novo.
• PM5: No other pathogenic missense variants at this amino acid residue have been identified.
• PM4: This variant does not cause a protein length change.
• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP7: This is not a synonymous or non-coding variant.
• PS4: Only 1 proband with POAG had been reported (PMID: 32476818), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PP3: This criterion was not met as BP4 has been met.

Approved on: 2023-07-05

Published on: 2023-07-05