Variant: NM_000261.2:c.1440C>G

CA343723150

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 34165818-5669-4223-ae50-86064c1ea325

Approved on: 2022-05-10

Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1440C>G
NC_000001.11:g.171636000G>C
CM000663.2:g.171636000G>C
NC_000001.10:g.171605140G>C
CM000663.1:g.171605140G>C
NC_000001.9:g.169871763G>C
NG_008859.1:g.21634C>G
ENST00000037502.11:c.1440C>G
ENST00000637303.1:c.235-2630G>C
ENST00000638471.1:c.*778C>G
ENST00000037502.10:c.1440C>G
ENST00000614688.1:c.*404C>G
NM_000261.1:c.1440C>G

Likely Pathogenic

• Met criteria codes: PP1 PP3 PM2_Supporting PS3_Moderate PS1

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

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1440C>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 4 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 18303389), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 18303389), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. The same amino acid change (p.Asn480Lys), resulting from a different nucleotide change (c.1440C>A, ClinVarID: 7951), was classified as pathogenic for JOAG by the ClinGen Glaucoma VCEP. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) (PS1). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS1, PS3_Moderate, PP1, PP3, PM2_Supporting.

Met criteria codes

• PP1: 4 segregations in 1 family, with JOAG, have been reported (PMID: 18303389), which fulfilled PP1 (3-4 meioses).
• PP3: The REVEL score = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on 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.
• PS3_Moderate: Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.
• PS1: The same amino acid change (p.Asn480Lys), resulting from a different nucleotide change (c.1440C>A, ClinVarID: 7951), was classified as pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. This variant is not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2).

Not Met criteria codes

• PM4: This variant does not cause a protein length change.
• PM5: No other missense variants at this amino acid residue have been identified.
• PM6: This variant has not been identified de novo.
• BS3: This criterion was not met as PS3_Moderate has been met.
• BS1: This criterion was not met as PM2_Supporting has been met.
• BP4: This criterion was not met as PP3 has been met.
• BP7: This is not a synonymous or non-coding variant.
• PS2: This variant has not been identified de novo.
• PS4: Only 1 proband with JOAG had been reported (PMID: 18303389), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• BA1: This criterion was not met as PM2_Supporting has been met.