NM_000261.2:c.1302C>T

CA1244046

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 5e813c7c-78b7-4ac8-bee9-1a1c7bcd112d

Approved on: 2023-06-01

Published on: 2023-06-01

HGVS expressions

NM_000261.2:c.1302C>T
NC_000001.11:g.171636138G>A
CM000663.2:g.171636138G>A
NC_000001.10:g.171605278G>A
CM000663.1:g.171605278G>A
NC_000001.9:g.169871901G>A
NG_008859.1:g.21496C>T
ENST00000037502.11:c.1302C>T
ENST00000637303.1:c.235-2492G>A
ENST00000638471.1:c.*640C>T
ENST00000037502.10:c.1302C>T
ENST00000614688.1:c.*266C>T
NM_000261.1:c.1302C>T

Uncertain Significance

• Not Met criteria codes: PM5 PM4 BA1 PM6 PM2 BS3 BS1 BP7 BP4 PS2 PS1 PS3 PS4 PP1 PP3

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1302C>T variant in MYOC is a synonymous variant (p.Gly434=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001307 (4 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). Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.12, which did not meet the ≤ 10 threshold for BP4 and a GERP score = 4.26 (threshold <0), not meeting BP7 and indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification 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): none

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) = 0.0001307 (4 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• 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) = 0.0001307 (4 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
• BP7: Although this synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 4.26 (threshold <0), indicating conservation at this site.
• BP4: Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.12, which does not meet the ≤ 10 threshold for BP4.
• 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: Although a proband with POAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.