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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CA1244313

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b83e6aa5-ebe9-4623-bf2a-e46c133f7023

HGVS expressions

NM_000261.2:c.210C>T
NC_000001.11:g.171652402G>A
CM000663.2:g.171652402G>A
NC_000001.10:g.171621542G>A
CM000663.1:g.171621542G>A
NC_000001.9:g.169888165G>A
NG_008859.1:g.5232C>T
ENST00000037502.11:c.210C>T
ENST00000638471.1:c.130+80C>T
ENST00000037502.10:c.210C>T
ENST00000614688.1:c.210C>T
NM_000261.1:c.210C>T

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 14
PM5 PM4 PS2 PS1 PS3 PS4 PM6 PM2 BA1 BP7 BS3 BS1 PP1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.210C>T variant in MYOC is a synonymous variant (p.Val70=). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175 (4 alleles out of 18,394), 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) = 6.623, 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 = 4.39 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with 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 -1 and to be classified 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): BP4.
Met criteria codes
BP4
The CADD score (v1.6) = 6.623, 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.
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 POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PM6
This variant has not been identified de novo.
PM2
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175 (4 alleles out of 18,394), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
BP7
Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 4.39 (threshold < 0), indicating conservation at this site.
BS3
No functional evidence has been found for this variant.
BS1
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0002175 (4 alleles out of 18,394), which did not meet the ≥ 0.001 threshold nor the ≥ 5 alleles necessary to meet BS1.
PP1
No segregations have been reported for this variant.
PP3
This is not a missense variant.
Approved on: 2023-02-15
Published on: 2023-02-15
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