The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.


Variant: NM_000261.2:c.985G>A

CA1244106

1111192 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: a54fc5d3-4800-4362-973d-282113cf7e9b

HGVS expressions

NM_000261.2:c.985G>A
NC_000001.11:g.171636455C>T
CM000663.2:g.171636455C>T
NC_000001.10:g.171605595C>T
CM000663.1:g.171605595C>T
NC_000001.9:g.169872218C>T
NG_008859.1:g.21179G>A
ENST00000037502.11:c.985G>A
ENST00000637303.1:c.235-2175C>T
ENST00000638471.1:c.*323G>A
ENST00000037502.10:c.985G>A
ENST00000614688.1:c.985G>A
NM_000261.1:c.985G>A
NM_000261.2(MYOC):c.985G>A (p.Val329Met)

Likely Benign

Met criteria codes 2
BS1 BS3_Supporting
Not Met criteria codes 13
PS2 PS1 PS3 PS4 BP4 BP7 BA1 PP3 PP1 PM5 PM4 PM6 PM2

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.985G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 329 (p.Val329Met). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.002523, which met the ≥ 0.001 threshold set for BS1 (63 alleles out of 24,968, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.466, 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: 11004290) demonstrated that the Val329Met protein had similar solubility 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 juvenile or 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 -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate.
Met criteria codes
BS1
The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.002523, which met the ≥ 0.001 threshold set for BS1 (63 alleles out of 24,968, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
BS3_Supporting
Applied at the BS3_Moderate level. A previous study (PMID: 11004290) demonstrated that the Val329Met protein had similar solubility 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
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 JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
BP4
The REVEL score = 0.466, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
BA1
This criterion was not met as BS1 has been met.
PP3
The REVEL score = 0.466, which did not meet the ≥ 0.7 threshold for PP3.
PP1
As BS1 was met, PP1 did not apply and segregations were not counted.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
PM2
This criterion was not met as BS1 has been met.
Approved on: 2022-02-21
Published on: 2022-07-11
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