The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000261.2(MYOC):c.1430T>A (p.Ile477Asn)

CA129023

30205 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 5fe3a673-abb3-4cde-a22c-baa28336fbe7
Approved on: 2022-05-10
Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1430T>A
NM_000261.2(MYOC):c.1430T>A (p.Ile477Asn)
NC_000001.11:g.171636010A>T
CM000663.2:g.171636010A>T
NC_000001.10:g.171605150A>T
CM000663.1:g.171605150A>T
NC_000001.9:g.169871773A>T
NG_008859.1:g.21624T>A
ENST00000037502.11:c.1430T>A
ENST00000637303.1:c.235-2620A>T
ENST00000638471.1:c.*768T>A
ENST00000037502.10:c.1430T>A
ENST00000614688.1:c.*394T>A
NM_000261.1:c.1430T>A
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Likely Pathogenic

Met criteria codes 4
PS3_Moderate PM2_Supporting PP1_Strong PS4_Supporting
Not Met criteria codes 11
BP4 BP7 PS1 PS2 PP3 PM5 PM4 PM6 BA1 BS1 BS3

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.1430T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 477 (p.Ile477Asn). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.534, 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. A previous study (PMID: 16466712) demonstrated that the Ile477Asn protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Supporting, PM2_Supporting
Met criteria codes
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Ile477Asn protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

PM2_Supporting
This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
PP1_Strong
34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family).
PS4_Supporting
2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), which met PS4_Supporting (≥ 2 probands).
Not Met criteria codes
BP4
The REVEL score = 0.534, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS2
This variant has not been identified de novo.
PP3
The REVEL score = 0.534, which did not meet the ≥ 0.7 threshold for PP3.
PM5
PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (1430T>G, Ile477Ser,ClinVarID: 7950) was not classified as likely pathogenic or pathogenic.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
BA1
This criterion was not met as PM2_Supporting has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
BS3
This criterion was not met as PS3_Moderate has been met.
Curation History
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