Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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CA1244059

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ca420800-6892-425d-96d9-42abca9e461b

HGVS expressions

NM_000261.2:c.1239C>T
NC_000001.11:g.171636201G>A
CM000663.2:g.171636201G>A
NC_000001.10:g.171605341G>A
CM000663.1:g.171605341G>A
NC_000001.9:g.169871964G>A
NG_008859.1:g.21433C>T
ENST00000037502.11:c.1239C>T
ENST00000637303.1:c.235-2429G>A
ENST00000638471.1:c.*577C>T
ENST00000037502.10:c.1239C>T
ENST00000614688.1:c.*203C>T
NM_000261.1:c.1239C>T

Likely Benign

Met criteria codes 2
BP7 BP4
Not Met criteria codes 13
BS3 BS1 BA1 PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 PM6 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1239C>T variant in MYOC is a synonymous variant (p.Leu413=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001633 (5 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). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.006 which met the ≤ 10 threshold for BP4, and the GERP score = -10.3 (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. 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 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/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -10.3 (threshold <0), indicating a lack of conservation at this site.
BP4
The CADD score (v1.6) = 0.006, 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
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) = 0.0001633 (5 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
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 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.
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
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001633 (5 alleles out of 30,616), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
Approved on: 2022-11-10
Published on: 2022-11-10
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