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.1150G>A

CA343724529

1342205 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 1d496dac-748e-4a00-954f-e320d270d7fa

HGVS expressions

NM_000261.2:c.1150G>A
NC_000001.11:g.171636290C>T
CM000663.2:g.171636290C>T
NC_000001.10:g.171605430C>T
CM000663.1:g.171605430C>T
NC_000001.9:g.169872053C>T
NG_008859.1:g.21344G>A
ENST00000037502.11:c.1150G>A
ENST00000637303.1:c.235-2340C>T
ENST00000638471.1:c.*488G>A
ENST00000037502.10:c.1150G>A
ENST00000614688.1:c.*114G>A
NM_000261.1:c.1150G>A
NM_000261.2(MYOC):c.1150G>A (p.Asp384Asn)

Likely Pathogenic

Met criteria codes 4
PP3 PS4_Supporting PM2_Supporting PP1_Strong
Not Met criteria codes 11
PS2 PS1 PS3 BA1 PM6 PM4 PM5 BS3 BS1 BP4 BP7

Evidence Links 0

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.1150G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 384 (p.Asp384Asn). 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 = 0.914, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 19234343) demonstrated that the Asp384Asn protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. 11 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 23826516, 19234343), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23826516, 11853639, 19234343), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 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, PP3, PS4_Supporting, PM2_Supporting.
Met criteria codes
PP3
The REVEL score = 0.914, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS4_Supporting
3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23826516, 11853639, 19234343), which met PS4_Supporting (≥ 2 probands).
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
11 segregations in 2 families, with JOAG or POAG, have been reported (PMIDs: 23826516, 19234343), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).
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
The study reporting functional evidence (PMID: 19234343) demonstrated that the Asp384Asn protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.
BA1
This criterion was not met as PM2_Supporting has been met.
PM6
This variant has not been identified de novo.
PM4
This variant does not cause a protein length change.
PM5
PM5_Supporting could not be applied to this variant as the other missense variants at the same amino acid residue (c.1150G>C, p.Asp384His, PMID: 29540704 and c.1151A>G, p.Asp384Gly, PMID: 22876119) were not classified as likely pathogenic or pathogenic.
BS3
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting has been met.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
Approved on: 2022-02-21
Published on: 2022-07-11
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