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.1130C>T

CA1244075

1342202 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c1e7d5a4-2952-462d-95e6-714568dcbcd0

HGVS expressions

NM_000261.2:c.1130C>T
NC_000001.11:g.171636310G>A
CM000663.2:g.171636310G>A
NC_000001.10:g.171605450G>A
CM000663.1:g.171605450G>A
NC_000001.9:g.169872073G>A
NG_008859.1:g.21324C>T
ENST00000037502.11:c.1130C>T
ENST00000637303.1:c.235-2320G>A
ENST00000638471.1:c.*468C>T
ENST00000037502.10:c.1130C>T
ENST00000614688.1:c.*94C>T
NM_000261.1:c.1130C>T
NM_000261.2(MYOC):c.1130C>T (p.Thr377Met)

Pathogenic

Met criteria codes 4
PS4 PP1_Strong PM2_Supporting PP3
Not Met criteria codes 11
PM5 PM4 PS2 PS1 PS3 PM6 BA1 BP7 BP4 BS3 BS1

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.1130C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 377 (p.Thr377Met). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.00006152 (1 allele out of 16 256), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.924, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, as the results were conflicting and inconclusive, PS3 was not applied. 47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PP3, PM2_Supporting
Met criteria codes
PS4
15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (≥ 15 probands). There are also several other probands from other studies not presented here.
PP1_Strong
47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were many more family studies published than presented here.
PM2_Supporting
The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.00006152 (1 allele out of 16 256), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
PP3
The REVEL score = 0.924, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
Not Met criteria codes
PM5
This pathogenic variant could not be used to apply PM5 to variants MYOC c.1130C>A p.Thr377Lys (Grantham score = 78) or c.1130C>G p.Thr377Arg (Grantham score = 71) which are located at the same amino acid residue, as the Grantham score was higher for this missense change (= 81). The other 2 variants could not be used to apply PM5 to c.1130C>T p.Thr377Met as they were not classified as likely pathogenic or pathogenic.
PM4
This variant does not cause a protein length change.
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 studies reporting functional evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, as the results were conflicting and inconclusive, PS3 was not applied.
The T377M protein is insoluble. This study meets the OddsPath threshold for PS3_Supporting (> 2.1) but not the threshold for PS3_Moderate (> 4.3). PubMed:11004290
The T377M protein demonstrated partial solubility. This study meets the OddsPath threshold for PS3_Supporting (> 2.1) but not the threshold for PS3_Moderate (> 4.3). PubMed:10545602
PM6
This variant has not been identified de novo.
BA1
This criterion was not met as PM2_Supporting has been met.
BP7
This is not a synonymous or non-coding variant.
BP4
This criterion was not met as PP3 has been met.
BS3
Although there were conflicting and inconclusive results, this variant may impact protein function (see PS3 comment).
The T377M protein is insoluble. This study meets the OddsPath threshold for PS3_Supporting (> 2.1) but not the threshold for PS3_Moderate (> 4.3). PubMed:11004290
The T377M protein demonstrated partial solubility. This study meets the OddsPath threshold for PS3_Supporting (> 2.1) but not the threshold for PS3_Moderate (> 4.3). PubMed:10545602
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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