NM_000261.2:c.384G>C

CA1244285

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: ae69f5f9-8e42-4f7e-a0ac-4f04c02a2770

HGVS expressions

NM_000261.2:c.384G>C
NC_000001.11:g.171652228C>G
CM000663.2:g.171652228C>G
NC_000001.10:g.171621368C>G
CM000663.1:g.171621368C>G
NC_000001.9:g.169887991C>G
NG_008859.1:g.5406G>C
ENST00000037502.11:c.384G>C
ENST00000638471.1:c.130+254G>C
ENST00000037502.10:c.384G>C
ENST00000614688.1:c.384G>C
NM_000261.1:c.384G>C

Uncertain Significance

• Met criteria codes: BP4 BP7 PM2_Supporting

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.384G>C variant in MYOC is a synonymous variant (p.Arg128=). 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. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 7.875 which met the ≤ 10 threshold for BP4, and the GERP score = -1.02 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests 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: 16148883), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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): BP4, BP7, PM2_Supporting.

Met criteria codes

• BP4: The CADD score (v1.6) = 7.875, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
• BP7: This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -1.02 (threshold < 0), indicating a lack of conservation at this site.
• 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

• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• PS3: No functional evidence has been found for this variant.
• PS4: Only 1 proband with POAG had been reported (PMID: 16148883), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• 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.

Approved on: 2023-06-01

Published on: 2023-06-01