Variant: NM_000261.2(MYOC):c.801T>C (p.Tyr267=)

CA1244154

875083 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: ac6507c4-e36f-49f4-8a9c-21fda0a56150

HGVS expressions

NM_000261.2:c.801T>C
NM_000261.2(MYOC):c.801T>C (p.Tyr267=)
NC_000001.11:g.171636639A>G
CM000663.2:g.171636639A>G
NC_000001.10:g.171605779A>G
CM000663.1:g.171605779A>G
NC_000001.9:g.169872402A>G
NG_008859.1:g.20995T>C
ENST00000037502.11:c.801T>C
ENST00000637303.1:c.235-1991A>G
ENST00000638471.1:c.*139T>C
ENST00000037502.10:c.801T>C
ENST00000614688.1:c.801T>C
NM_000261.1:c.801T>C

Likely Benign

• Met criteria codes: BP7 BP4

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

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.801T>C variant in MYOC is a synonymous variant (p.Tyr267=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0003267 (10 alleles out of 30,612), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 3.164 which met the ≤ 10 threshold for BP4, and the GERP score = -3.31 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma, thus PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, BP7.

Met criteria codes

• BP7: This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -3.31 (threshold < 0), indicating a lack of conservation at this site.
• BP4: The CADD score (v1.6) = 3.164, 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

• 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) = 0.0003267 (10 alleles out of 30,612), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• PS4: This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma.
• 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.
• 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) = 0.0003267 (10 alleles out of 30,612), which did not meet the ≥ 0.001 threshold set for BS1.

Approved on: 2023-04-04

Published on: 2023-04-04