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.878C>A

CA1244131

876939 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: e230c8d5-45dc-4b84-9311-2628193b310b

HGVS expressions

NM_000261.2:c.878C>A
NC_000001.11:g.171636562G>T
CM000663.2:g.171636562G>T
NC_000001.10:g.171605702G>T
CM000663.1:g.171605702G>T
NC_000001.9:g.169872325G>T
NG_008859.1:g.21072C>A
ENST00000037502.11:c.878C>A
ENST00000637303.1:c.235-2068G>T
ENST00000638471.1:c.*216C>A
ENST00000037502.10:c.878C>A
ENST00000614688.1:c.878C>A
NM_000261.1:c.878C>A
NM_000261.2(MYOC):c.878C>A (p.Thr293Lys)

Likely Benign

Met criteria codes 2
BS3_Supporting BS1
Not Met criteria codes 13
BP7 BP4 BA1 PS2 PS1 PS3 PS4 PP1 PP3 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.878C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Lysine at amino acid 293 (p.Thr293Lys). The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.002493, which met the ≥ 0.001 threshold set for BS1 (25 alleles out of 10,030, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.541, 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 Thr293Lys protein had similar 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. As BS1 was met, PP1 did not apply and segregations were not counted. 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 -6 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): BS1, BS3_Moderate.
Met criteria codes
BS3_Supporting
Applied at the BS3_Moderate level. A previous study (PMID: 16466712) demonstrated that the Thr293Lys protein had similar 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.

BS1
The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.002493, which met the ≥ 0.001 threshold set for BS1 (25 alleles out of 10,030, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
Not Met criteria codes
BP7
This is not a synonymous or non-coding variant.
BP4
The REVEL score = 0.541, which did not meet the ≤ 0.15 threshold required for BP4.
BA1
This criterion was not met as BS1 has been met.
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.
PP1
As BS1 was met, PP1 did not apply and segregations were not counted.
PP3
The REVEL score = 0.541, which did not meet the ≥ 0.7 threshold for PP3.
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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