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.624C>G

CA1244210

876020 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 7a5f7517-f4d3-4df2-b595-38ea5f9092dd
Approved on: 2022-02-21
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.624C>G
NC_000001.11:g.171638703G>C
CM000663.2:g.171638703G>C
NC_000001.10:g.171607843G>C
CM000663.1:g.171607843G>C
NC_000001.9:g.169874466G>C
NG_008859.1:g.18931C>G
ENST00000037502.11:c.624C>G
ENST00000637303.1:c.308G>C
ENST00000638471.1:c.154C>G
ENST00000037502.10:c.624C>G
ENST00000614688.1:c.624C>G
NM_000261.1:c.624C>G
NM_000261.2(MYOC):c.624C>G (p.Asp208Glu)
More

Likely Benign

Met criteria codes 2
BS1 BP4
Not Met criteria codes 13
BA1 BS3 BP7 PS2 PS1 PS3 PS4 PP1 PP3 PM6 PM2 PM4 PM5

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.624C>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 208 (p.Asp208Glu). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.007468, which met the ≥ 0.001 threshold set for BS1 (149 alleles out of 19,952, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.126, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. 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 -5 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, BP4.
Met criteria codes
BS1
The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.007468, which met the ≥ 0.001 threshold set for BS1 (149 alleles out of 19,952, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
BP4
The REVEL score = 0.126, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function.
Not Met criteria codes
BA1
This criterion was not met as BS1 has been met.
BS3
The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied.

BP7
This is not a synonymous or non-coding variant.
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
Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.

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
This criterion was not met as BP4 has been met.
PM6
This variant has not been identified de novo.
PM2
This criterion was not met as BS1 has been met.
PM4
This variant does not cause a protein length change.
PM5
PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.622G>T, p.Asp208Tyr, PMID:32945492) was not classified as likely pathogenic or pathogenic.
Curation History
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