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Variant: NM_000261.2(MYOC):c.573T>A (p.Thr191=)

CA1244254

877000 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: d8a50bc1-ba36-4cc6-95f3-408fe83c0955

HGVS expressions

NM_000261.2:c.573T>A
NM_000261.2(MYOC):c.573T>A (p.Thr191=)
NC_000001.11:g.171652039A>T
CM000663.2:g.171652039A>T
NC_000001.10:g.171621179A>T
CM000663.1:g.171621179A>T
NC_000001.9:g.169887802A>T
NG_008859.1:g.5595T>A
ENST00000037502.11:c.573T>A
ENST00000638471.1:c.130+443T>A
ENST00000037502.10:c.573T>A
ENST00000614688.1:c.573T>A
NM_000261.1:c.573T>A

Uncertain Significance

Met criteria codes 3
BP4 BP7 PM2_Supporting
Not Met criteria codes 12
PS4 PS2 PS1 PS3 BA1 PP1 PP3 PM5 PM4 PM6 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.573T>A variant in MYOC is a synonymous variant (p.Thr191=). The highest minor allele frequency of this variant was in the European non-Finnish) population of gnomAD (v2.1.1) = 0.00002639 (3 alleles out of 113674), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.285 which met the ≤ 10 threshold for BP4, and the GERP score = -3.14 (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 -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, BP7, PM2_Supporting
Met criteria codes
BP4
The CADD score (v1.6) = 0.285, 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 = -3.14 (threshold <0), indicating a lack of conservation at this site.
PM2_Supporting
The highest minor allele frequency of this variant was in the European non-Finnish) population of gnomAD (v2.1.1) = 0.00002639 (3 alleles out of 113674), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
Not Met criteria codes
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.
BA1
This criterion was not met as PM2_Supporting has been met.
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.
BS3
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2023-05-03
Published on: 2023-05-03
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