Variant: NM_000261.2(MYOC):c.304T>A (p.Leu102Met)

CA10608379

293720 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 084e62a6-3c84-4808-95c3-4847e6b20e7c

HGVS expressions

NM_000261.2:c.304T>A
NM_000261.2(MYOC):c.304T>A (p.Leu102Met)
NC_000001.11:g.171652308A>T
CM000663.2:g.171652308A>T
NC_000001.10:g.171621448A>T
CM000663.1:g.171621448A>T
NC_000001.9:g.169888071A>T
NG_008859.1:g.5326T>A
ENST00000037502.11:c.304T>A
ENST00000638471.1:c.130+174T>A
ENST00000037502.10:c.304T>A
ENST00000614688.1:c.304T>A
NM_000261.1:c.304T>A

Uncertain Significance

• Met criteria codes: BP4 PM2_Supporting

• Not Met criteria codes: PS4 PS2 PS1 PS3 BP7 BA1 PP1 PP3 PM5 PM4 PM6 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.304T>A variant in MYOC is a missense variant predicted to cause substitution of Leucine by Methionine at amino acid 102 (p.Leu102Met). 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 = 0.071, 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. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant of the control cohort, thus PS4 did not apply. 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

• BP4: The REVEL score = 0.071, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact 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

• PS4: This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma.
• 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.
• BP7: This is not a synonymous or non-coding 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.
• PM5: No other missense variants at this amino acid residue have been identified.
• 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: 2023-08-08

Published on: 2023-08-08