Variant: NM_000261.2:c.1105T>C

CA343724711

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: f99e041c-8dcd-4b30-a4bd-cf14e519da75

Approved on: 2022-11-10

Published on: 2022-11-10

HGVS expressions

NM_000261.2:c.1105T>C
NC_000001.11:g.171636335A>G
CM000663.2:g.171636335A>G
NC_000001.10:g.171605475A>G
CM000663.1:g.171605475A>G
NC_000001.9:g.169872098A>G
NG_008859.1:g.21299T>C
ENST00000037502.11:c.1105T>C
ENST00000637303.1:c.235-2295A>G
ENST00000638471.1:c.*443T>C
ENST00000037502.10:c.1105T>C
ENST00000614688.1:c.*69T>C
NM_000261.1:c.1105T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PS4_Supporting PP3

• Not Met criteria codes: BS3 BS1 BP7 BP4 PS2 PS1 PS3 PM5 PM4 BA1 PM6 PP1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1105T>C variant in MYOC is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 369 (p.Phe369Leu). 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 = 0.872, 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. Only 2 segregations had been reported for primary open angle glaucoma (PMIDs: 28564705, 15534471), not meeting the ≥ 3 segregations required for PP1. 2 probands with POAG have been reported carrying this variant (PMIDs: 15534471, 28564705), which met PS4_Supporting (≥ 2 probands). 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, 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.
• PS4_Supporting: 2 probands with POAG have been reported carrying this variant (PMIDs: 15534471, 28564705), which met PS4_Supporting (≥ 2 probands).
• PP3: The REVEL score = 0.872, 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: PS1 could not be applied to this variant as the same amino acid change (p.Phe369Leu), resulting from a different nucleotide change (c.1107C>G), was not classified as likely pathogenic or pathogenic.
• PS3: No functional evidence has been found for this variant.
• 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 criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.
• PP1: Only 2 segregations had been reported for primary open angle glaucoma (PMIDs: 28564705, 15534471), not meeting the ≥ 3 segregations required for PP1.