Variant: NM_000261.2(MYOC):c.864C>T (p.Ile288=)

CA1244136

874154 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 61aa02eb-f312-4cfd-9268-ac6b223edaed

HGVS expressions

NM_000261.2:c.864C>T
NM_000261.2(MYOC):c.864C>T (p.Ile288=)
NC_000001.11:g.171636576G>A
CM000663.2:g.171636576G>A
NC_000001.10:g.171605716G>A
CM000663.1:g.171605716G>A
NC_000001.9:g.169872339G>A
NG_008859.1:g.21058C>T
ENST00000037502.11:c.864C>T
ENST00000637303.1:c.235-2054G>A
ENST00000638471.1:c.*202C>T
ENST00000037502.10:c.864C>T
ENST00000614688.1:c.864C>T
NM_000261.1:c.864C>T

Likely Benign

• Met criteria codes: BS1 BP4 BP7

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

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.864C>T variant in MYOC is a synonymous variant (p.Ile288=). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.003060, which met the ≥ 0.001 threshold set for BS1 (61 alleles out of 19 934, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.181 which met the ≤ 10 threshold for BP4, and the GERP score = -6.07 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BP4, BP7.

Met criteria codes

• BS1: The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.003060, which met the ≥ 0.001 threshold set for BS1 (61 alleles out of 19 934, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
• BP4: The CADD score (v1.6) = 0.181 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.
• BP7: This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -6.07 (threshold <0), indicating a lack of conservation at this site.

Not Met criteria codes

• 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.
• PS4: Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP3: This is not a missense variant.
• PP1: As BS1 was met, PP1 did not apply and segregations were not counted.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• PM6: This variant has not been identified de novo.
• PM2: This criterion was not met as BS1 has been met.
• BA1: This criterion was not met as BS1 has been met.
• BS3: No functional evidence has been found for this variant.

Approved on: 2022-02-21

Published on: 2022-07-11