Variant: NM_000261.2:c.1138G>A

CA343724574

1342204 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: baa5ecd0-f7de-40a3-bab1-250c8c33c613

Approved on: 2022-02-21

Published on: 2022-02-21

HGVS expressions

NM_000261.2:c.1138G>A
NC_000001.11:g.171636302C>T
CM000663.2:g.171636302C>T
NC_000001.10:g.171605442C>T
CM000663.1:g.171605442C>T
NC_000001.9:g.169872065C>T
NG_008859.1:g.21332G>A
ENST00000037502.11:c.1138G>A
ENST00000637303.1:c.235-2328C>T
ENST00000638471.1:c.*476G>A
ENST00000037502.10:c.1138G>A
ENST00000614688.1:c.*102G>A
NM_000261.1:c.1138G>A

Uncertain Significance

• Met criteria codes: PP3 PS4_Supporting PM2_Supporting

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1138G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 380 (p.Asp380Asn). 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 = 0.842, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID: 12362081), 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 juvenile 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

• PP3: The REVEL score = 0.842, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PS4_Supporting: 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 12362081), which met PS4_Supporting (≥ 2 probands).
• 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

• PP1: No segregations have been reported for this variant.
• PM6: This variant has not been identified de novo.
• PM5: PM5_Supporting could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (= 23) than the score for the different missense changes at the same amino acid residue determined to be likely pathogenic or pathogenic (without the application of PM5_Supporting) by the ClinGen Glaucoma VCEP (c.1138G>C, p.Asp380His, Grantham score=81 and c.1139A>C, p.Asp380Ala, Grantham score=126).
• PM4: This variant does not cause a protein length change.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS2: This variant has not been identified de novo.
• PS3: No functional evidence has been found for this variant.
• BA1: 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.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BS3: No functional evidence has been found for this variant.