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.856T>C

CA343725818

1342197 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: de55d474-3c2c-44cd-b924-6d03e84329bc

HGVS expressions

NM_000261.2:c.856T>C
NC_000001.11:g.171636584A>G
CM000663.2:g.171636584A>G
NC_000001.10:g.171605724A>G
CM000663.1:g.171605724A>G
NC_000001.9:g.169872347A>G
NG_008859.1:g.21050T>C
ENST00000037502.11:c.856T>C
ENST00000637303.1:c.235-2046A>G
ENST00000638471.1:c.*194T>C
ENST00000037502.10:c.856T>C
ENST00000614688.1:c.856T>C
NM_000261.1:c.856T>C
NM_000261.2(MYOC):c.856T>C (p.Trp286Arg)

Uncertain Significance

Met criteria codes 4
PP3 PS3_Moderate PS4_Supporting PM2_Supporting
Not Met criteria codes 11
PS2 PS1 BP4 BP7 BA1 PP1 PM5 PM4 PM6 BS3 BS1

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.856T>C variant in MYOC is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 286 (p.Trp286Arg). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00005811 (2 alleles out of 34,418), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.917, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Trp286Arg 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. Only 2 segregations had been reported for primary open angle glaucoma (E. Souzeau pers. comm.), not meeting the ≥ 3 segregations required for PP1. 5 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23453510, 22879734, 9535666, E. Souzeau pers. comm.), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting.
Met criteria codes
PP3
The REVEL score = 0.917, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Trp286Arg 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.
PS4_Supporting
5 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23453510, 22879734, 9535666, E. Souzeau pers. comm.), which met PS4_Supporting (≥ 2 probands).
PM2_Supporting
The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00005811 (2 alleles out of 34,418), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
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.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
BA1
This criterion was not met as PM2_Supporting has been met.
PP1
Only 2 segregations had been reported for POAG (E. Souzeau pers. comm.), not meeting the ≥ 3 segregations required for PP1.
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.
BS3
This criterion was not met as PS3_Moderate has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2022-02-21
Published on: 2022-07-11
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