Variant: NM_000261.2:c.1111T>G

CA343724686

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 26ec0e40-daee-4c45-9d87-22e7bcbd14e5

Approved on: 2023-05-03

Published on: 2023-05-03

HGVS expressions

NM_000261.2:c.1111T>G
NC_000001.11:g.171636329A>C
CM000663.2:g.171636329A>C
NC_000001.10:g.171605469A>C
CM000663.1:g.171605469A>C
NC_000001.9:g.169872092A>C
NG_008859.1:g.21305T>G
ENST00000037502.11:c.1111T>G
ENST00000637303.1:c.235-2301A>C
ENST00000638471.1:c.*449T>G
ENST00000037502.10:c.1111T>G
ENST00000614688.1:c.*75T>G
NM_000261.1:c.1111T>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PP1 PP3

• Not Met criteria codes: BS3 BS1 BP7 BP4 PS2 PS1 PS3 PS4 PM5 PM4 BA1 PM6

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1111T>G variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Aspartic Acid at amino acid 371 (p.Tyr371Asp). 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 = 0.892, 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. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 19784393), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 19784393), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, 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.
• PP1: 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 19784393), which fulfilled PP1 (3-4 meioses).
• PP3: The REVEL score = 0.892, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

Not Met criteria codes

• 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.
• BP4: This criterion was not met as PP3 has been met.
• 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: Only 1 proband with JOAG had been reported (PMID: 19784393), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1111T>C, p.Tyr371His, ClinVarID: 242274) was not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.