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Variant: NM_000261.2(MYOC):c.612G>A (p.Thr204=)

CA1244213

876021 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 50fa855a-4a65-4e61-829e-d30bd719d49f
Approved on: 2023-11-14
Published on: 2023-11-14

HGVS expressions

NM_000261.2:c.612G>A
NM_000261.2(MYOC):c.612G>A (p.Thr204=)
NC_000001.11:g.171638715C>T
CM000663.2:g.171638715C>T
NC_000001.10:g.171607855C>T
CM000663.1:g.171607855C>T
NC_000001.9:g.169874478C>T
NG_008859.1:g.18919G>A
ENST00000037502.11:c.612G>A
ENST00000637303.1:c.320C>T
ENST00000638471.1:c.142G>A
ENST00000037502.10:c.612G>A
ENST00000614688.1:c.612G>A
NM_000261.1:c.612G>A
More

Likely Benign

Met criteria codes 3
BP7 BP4 BS3_Supporting
Not Met criteria codes 12
PS4 PS2 PS1 PS3 PP1 PP3 PM5 PM4 PM6 PM2 BA1 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.612G>A variant in MYOC is a synonymous variant (p.Thr204=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 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) = 0.145 which met the ≤ 10 threshold for BP4, and the GERP score = -5.55 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. A previous study (PMID: 35196929) demonstrated that the Thr204= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein 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. Additionally, as PM2_Supporting was not met, PS4 did not apply. In summary, this variant met the criteria to receive a score of -3 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, BS3_Supporting
Met criteria codes
BP7
This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -5.55 (threshold <0), indicating a lack of conservation at this site.
BP4
The CADD score (v1.6) = 0.145, 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.
BS3_Supporting
A previous study (PMID: 35196929) demonstrated that the Thr204= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function.

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. Additionally, as PM2_Supporting was not met, PS4 did not apply.
PS2
This variant has not been identified de novo.
PS1
This variant does not involve an amino acid change.
PS3
This criterion was not met as BS3_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.
PM2
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 alleles out of 30,616), 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).
BS1
The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0001960 (6 alleles out of 30,616), which did not meet the ≥ 0.001 threshold set for BS1.
Curation History
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