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Variant: NM_000261.2(MYOC):c.1334C>T (p.Ala445Val)

CA1244040

631578 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: c08c169f-8ad9-4b17-a830-e50b12425e7d
Approved on: 2022-03-07
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.1334C>T
NM_000261.2(MYOC):c.1334C>T (p.Ala445Val)
NC_000001.11:g.171636106G>A
CM000663.2:g.171636106G>A
NC_000001.10:g.171605246G>A
CM000663.1:g.171605246G>A
NC_000001.9:g.169871869G>A
NG_008859.1:g.21528C>T
ENST00000037502.11:c.1334C>T
ENST00000637303.1:c.235-2524G>A
ENST00000638471.1:c.*672C>T
ENST00000037502.10:c.1334C>T
ENST00000614688.1:c.*298C>T
NM_000261.1:c.1334C>T
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Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 1
BS3_Supporting
Not Met criteria codes 14
BS1 BP7 BP4 PS2 PS1 PS3 PS4 BA1 PP1 PP3 PM6 PM2 PM5 PM4

Evidence Links 2

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.1334C>T variant in MYOC is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 445 (p.Ala445Val). The highest minor allele frequency of this variant was in the non-Finnish European population of gnomAD (v2.1.1) = 0.0003406 (44 alleles out of 129,196), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.472, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Ala445Val protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein 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 -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): BS3_Moderate.
Met criteria codes
BS3_Supporting
Applied at the BS3_Moderate level. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Ala445Val protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function.

Not Met criteria codes
BS1
The highest minor allele frequency of this variant was in the non-Finnish European population of gnomAD (v2.1.1) = 0.0003406 (44 alleles out of 129,196), which did not meet the ≥ 0.001 threshold set for BS1.
BP7
This is not a synonymous or non-coding variant.
BP4
The REVEL score = 0.472, which did not meet the ≤ 0.15 threshold required for BP4.
PS2
This variant has not been identified de novo.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS3
This criterion was not met as BS3_Moderate has been met.
PS4
Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
BA1
This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
PP1
No segregations have been reported for this variant.
PP3
The REVEL score = 0.472, which did not meet the ≥ 0.7 threshold for PP3.
PM6
This variant has not been identified de novo.
PM2
The highest minor allele frequency of this variant was in the non-Finnish European population of gnomAD (v2.1.1) = 0.0003406 (44 alleles out of 129,196), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
Curation History
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