The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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CA1244099

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 99d8e0c6-0d3d-4c86-ba85-d38c63b88971

HGVS expressions

NM_000261.2:c.1001T>C
NC_000001.11:g.171636439A>G
CM000663.2:g.171636439A>G
NC_000001.10:g.171605579A>G
CM000663.1:g.171605579A>G
NC_000001.9:g.169872202A>G
NG_008859.1:g.21195T>C
ENST00000037502.11:c.1001T>C
ENST00000637303.1:c.235-2191A>G
ENST00000638471.1:c.*339T>C
ENST00000037502.10:c.1001T>C
ENST00000614688.1:c.1001T>C
NM_000261.1:c.1001T>C

Uncertain Significance

Met criteria codes 3
PP1 PP3 PM2_Supporting
Not Met criteria codes 12
PS2 PS1 PS3 PS4 BP4 BP7 BA1 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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1001T>C variant in MYOC is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 334 (p.Leu334Pro). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.936, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 18385784), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 18385784), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 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): PP1, PP3, PM2_Supporting.
Met criteria codes
PP1
3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 18385784), which fulfilled PP1 (3-4 meioses).
PP3
The REVEL score = 0.936, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PM2_Supporting
The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), 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.
PS3
No functional evidence has been found for this variant.
PS4
Only 1 proband with JOAG had been reported (PMID: 18385784), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
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.
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
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2023-07-05
Published on: 2023-07-05
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