NM_000261.2:c.1290C>T

CA1244048

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 2b6ac23d-3cec-4245-8579-f483c947997f

Approved on: 2023-02-15

Published on: 2023-02-15

HGVS expressions

NM_000261.2:c.1290C>T
NC_000001.11:g.171636150G>A
CM000663.2:g.171636150G>A
NC_000001.10:g.171605290G>A
CM000663.1:g.171605290G>A
NC_000001.9:g.169871913G>A
NG_008859.1:g.21484C>T
ENST00000037502.11:c.1290C>T
ENST00000637303.1:c.235-2480G>A
ENST00000638471.1:c.*628C>T
ENST00000037502.10:c.1290C>T
ENST00000614688.1:c.*254C>T
NM_000261.1:c.1290C>T

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: PM5 PM4 BA1 PM6 PM2 BS3 BS1 BP7 PS4 PS2 PS1 PS3 PP1 PP3

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.1290C>T variant in MYOC is a synonymous variant (p.Phe430=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The CADD score (v1.6) = 6.961, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 2.25 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 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): BP4.

Met criteria codes

• BP4: The CADD score (v1.6) = 6.961, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.

Not Met criteria codes

• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• PM6: This variant has not been identified de novo.
• PM2: The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
• BS3: No functional evidence has been found for this variant.
• BS1: The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
• BP7: Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 2.25 (threshold < 0), indicating conservation at this site.
• PS4: Only 1 proband with JOAG had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• PS3: No functional evidence has been found for this variant.
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.