Evidence Repository
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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  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.

Variant: NM_000261.2:c.731G>T

CA1244164

1342209 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7950d5a7-12a0-4066-9380-cd03dfacaaef
Approved on: 2022-02-21
Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.731G>T
NC_000001.11:g.171636709C>A
CM000663.2:g.171636709C>A
NC_000001.10:g.171605849C>A
CM000663.1:g.171605849C>A
NC_000001.9:g.169872472C>A
NG_008859.1:g.20925G>T
ENST00000037502.11:c.731G>T
ENST00000637303.1:c.235-1921C>A
ENST00000638471.1:c.*69G>T
ENST00000037502.10:c.731G>T
ENST00000614688.1:c.731G>T
NM_000261.1:c.731G>T
NM_000261.2(MYOC):c.731G>T (p.Gly244Val)

Uncertain Significance

Met criteria codes 3
PS4_Supporting PP3 PM2_Supporting
Not Met criteria codes 12
BP7 BP4 PS2 PS1 PS3 PP1 PM6 PM4 PM5 BA1 BS3 BS1

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.731G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 244 (p.Gly244Val). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.00004466 (5 alleles out of 111,968), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.748, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val 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. No segregations have been reported in individuals carrying this variant and no other likely pathogenic or pathogenic variant. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID:17210859, E. Souzeau (pers. comm.)), which met PS4_Supporting (≥ 2 probands). 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting.
Met criteria codes
PS4_Supporting
2 probands with POAG have been reported carrying this variant (PMID:17210859, E. Souzeau (pers. comm.)), which met PS4_Supporting (≥ 2 probands).
PP3
The REVEL score = 0.748, 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 European (non-Finnish) population of gnomAD (v2.1.1) = 0.00004466 (5 alleles out of 111,968), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. Although this variant had been observed once in the "other" population (1 allele out of 6,004, MAF = 0.0001666) , there were less than 10,000 alleles in this population , which did not meet the allele threshold for criterion.
Not Met criteria codes
BP7
This is not a synonymous or non-coding variant.
BP4
This criterion was not met as PP3 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
Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
The G244V protein is secreted. This study does not meet the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:27092720
PP1
No segregations have been reported in individuals carrying this variant and no other likely pathogenic or pathogenic variant.
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.730G>A, p.Gly244Arg, PMID:22933836 and c.731G>C, p.Gly244Ala, PMID:12442283) were not classified as likely pathogenic or pathogenic.
BA1
This criterion was not met as PM2_Supporting has been met.
BS3
The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val 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.
The G244V protein is secreted. This study does not meet the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:27092720
BS1
This criterion was not met as PM2_Supporting has been met.
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