The MYOC NM_000261.2:c.1102C>T (NP_000252.1:p.(Gln368Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV50674786, n = 4 times). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Likely Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Glaucoma Variant Curation Expert Panel; ClinVar ID 7949).
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYOC encodes myocilin, a protein thought to support the cell’s internal structural framework and found in several eye tissues, including the trabecular meshwork that helps regulate eye pressure. Changes in MYOC can cause hereditary juvenile-onset open-angle glaucoma; no established role in cancer is known.
The recorded framework is ClinGen MYOC VCEP v2.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, Strong: the exact p.Gln368Ter amino-acid change is established as Pathogenic by a ClinVar expert panel.
Met at moderate strength: p.(Gln368Ter) removes 137 of 505 residues (27.1%), exceeding 10%, within the olfactomedin domain at amino acids 246-502.
Not applicable: the MYOC VCEP explicitly prohibits use of PP5 under its approved criterion specifications.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong, PM4 moderate, and PP5 supporting total 7 points under the MYOC VCEP Version 2.1 framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1,870 / 1,613,974 alleles. Recorded AF 0.00115863. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 0.00111047; MAF= 0.11105%, 314/282762 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00334422; MAF= 0.33442%, 84/25118 alleles, homozygotes = 0); grpmax FAF= 0.00139395.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.015. Refer to the recorded PP3/BP4 rationale for interpretation.
11 Pathogenic · 4 Likely pathogenic · 1 Likely benign. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV50674786, n = 4 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen MYOC VCEP v2.1, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 4 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Only PVS1, PM4, and BP3 were assessed under the MYOC VCEP Version 2.1 specifications.
PM4 is met at moderate strength because the exon 3 nonsense variant truncates 27.1% of the 505-amino-acid protein within the conserved olfactomedin domain.
PVS1 and BP3 are not applicable because the VCEP CSPEC entries explicitly designate both criteria as Not Applicable.
Under the MYOC VCEP, PS2 cannot be assessed without documented confirmed de novo evidence and required parental evaluation; PM6 and BS4 are not applicable; PP1 cannot be assigned because the available reports do not provide an auditable VCEP-countable meiosis total.
PS4 has qualifying affected-proband observations, but its VCEP-mandated PM2 prerequisite fails because gnomAD v4.1 allele frequency is 0.00115863 versus the VCEP PM2 threshold of ≤ 0.0001.
PP4, PP5, BP5, and BP6 are not applicable under the MYOC VCEP specifications.
No criteria match.
The variant is NM_000261.2:c.1102C>T, p.(Gln368Ter), and ClinVar Variation ID 7949 records this exact amino-acid change as Pathogenic with an expert-panel review status. This satisfies the MYOC VCEP PS1 Strong rule for the same amino-acid change as a previously established pathogenic variant.
Same amino acid change as previously established pathogenic variant
NM_000261.2:c.1102C>T is a nonsense variant producing NP_000252.1:p.(Gln368Ter) in exon 3. The reference protein is 505 amino acids and the predicted truncated product is 368 amino acids, eliminating 137 residues (27.1%), which is greater than 10%. Residue 368 lies within the VCEP-defined conserved olfactomedin domain at amino acids 246-502. Therefore the VCEP PM4 moderate rule for truncating variants involving >10% of the protein within this domain is met.
In-frame del/ins, stop-loss variants and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).
Expert panel ClinGen Glaucoma Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The MYOC VCEP permits PS4 through a quasi-case-control count of clinically assessed JOAG/POAG probands from multiple independent studies, but explicitly requires PM2 to be met. Variant-specific literature documents 5 unrelated POAG probands in PMID:11803488 and 2 affected probands in two independent families in PMID:11004290, already reaching the VCEP's moderate count threshold of ≥ 6 probands; PMID:9005853 additionally reports Gln361STOP in 6/227 familial glaucoma patients and 3/103 unselected glaucoma patients, with 1/380 general-population individuals. I also checked the available abstract for PMID:23029558, which confirms a meta-analysis of 32 case-control studies involving Q368X but does not provide a variant-specific estimate in the available text. For the reported counts, I computed case-control effect estimates: PMID:9005853, 3/103 cases versus 1/380 controls gives OR=11.37, 95% CI 1.17-110.49; PMID:11803488, 5/117 cases versus 0/50 controls gives a Haldane-Anscombe corrected OR=4.94, 95% CI 0.27-91.01. However, gnomAD v4.1 reports AF=0.00115863 and grpmax FAF=0.00127788, so the VCEP-required PM2 prerequisite (allele frequency ≤ 0.0001) is not met; therefore PS4 cannot be applied under this VCEP even though the proband evidence is present.
Case-control data for _MYOC_ variants is limited due to control cohorts often being too small to reflect the true prevalence of variants in a true control population. Instead, the Glaucoma VCEP recommends using PS4 for counting probands from multiple independent studies using a “quasi case-control study” approach. ... * Probands need to be clinically assessed and have JOAG or POAG ... * PM2 needs to be met (due to incomplete penetrance, late age of onset of glaucoma and the rate of undiagnosed glaucoma in the general population, pathogenic variants may be present in population databases) ... ≥ 6 probands from multiple independent studies.
The governing VCEP PM2 rule requires allele frequency ≤0.0001 in population databases, uses the highest allele frequency, and applies only to populations with at least 10,000 alleles. The highest observed frequency is 0.003799 in the gnomAD v2.1 non-cancer exome-derived Finnish XY subgroup (49/12,898 alleles), while the qualifying overall populations exceed 10,000 alleles; the observed frequency is above the PM2 threshold. The gnomAD v2.1 non-cancer exome total AF is 0.00107234 (254/236,866 alleles), and gnomAD v4.1 total AF is 0.00115863 (1,870/1,613,974 alleles), also both above threshold.
Allele frequency ≤ 0.0001 in population databases.
The governing VCEP BA1 threshold is allele frequency ≥0.01, using the highest allele frequency in population databases. The highest observed frequency available for this variant is 0.003799 in the gnomAD v2.1 non-cancer exome-derived Finnish XY subgroup (49/12,898 alleles; 0.3799%), with 0.003551 in gnomAD v4.1 all-comers Finnish XY (120/33,796 alleles); these values are below 0.01. The qualifying subgroup has more than 2,000 observed alleles and at least 5 variant alleles, so the dataset-quality condition is satisfied, but the frequency threshold is not.
Allele frequency ≥ 0.01 in population databases.
The VCEP requires confirmed de novo status to combine PS2 and PM6 under PS2, with both maternity and paternity proven and parents clinically assessed without glaucoma. The available evidence reports familial carriers and affected relatives, but does not document a confirmed de novo occurrence for this variant in a JOAG or POAG proband. Therefore the VCEP PS2 thresholds cannot be evaluated.
Both maternity and paternity need to be proven for confirmed de novo variants. ... Parents need to be clinically assessed and not have a diagnosis of glaucoma (If a parent has suspicious signs of glaucoma, the age and the severity of the symptoms should be taken into account before applying criteria). ... * 1 confirmed de novo in POAG * Or ≥2 assumed _de novo_ in POAG * Or 1 assumed _de novo_ in JOAG
The VCEP permits PS3 for MYOC stability, solubility, or secretion assays, but requires both negative and positive controls, technical and/or biological replicates, selection of the best-validated assay, and OddsPath calibration. Variant-specific studies report damaging functional findings: Q368X was insoluble and retained intracellularly in human trabecular meshwork cells (PMID:26396484), was not secreted in COS-7 and human trabecular meshwork cells (PMID:16466712), and produced insoluble protein in a HEK293T Triton X-100 solubility assay (PMID:11004290). However, the available evidence does not provide an OddsPath value or establish the required control and replicate characteristics for a qualifying assay; therefore the VCEP strength thresholds cannot be evaluated and PS3 is not assessed.
PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates. ... Assays with OddsPath >2.1 as per the SVI recommendations.[<sup>1</sup>](#PMID_31892348)
The VCEP PP1 rule counts only clinically assessed phenotype-positive genotype-positive individuals and obligate carriers with phenotype-positive status, using informative meioses across families; it requires at least 3 meioses for Supporting evidence. Relevant reports show Q368STOP in affected carriers, including 2/2 affected members in one family and 6/6 in another, and describe 29 carriers with POAG or ocular hypertension across eight pedigrees. However, the available extracts do not provide the pedigree relationships or a validated count of informative meioses under the VCEP counting rules. The same literature reports genotype-positive phenotype-negative carriers and non-carrier POAG cases, so those individuals cannot be counted as segregations. PP1 cannot be assigned a strength without an auditable meiosis count.
* Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations. * Individuals who are genotype positive/phenotype negative and individuals who are genotype negative/phenotype negative should not be counted * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma. ... ≥ 3 meioses regardless of the number of families
The VCEP permits BS3 only for variants showing solubility or secretion in functional assays, with negative and positive controls, technical and/or biological replicates, best-validated assay selection, and OddsPath below the applicable threshold. The available variant-specific studies instead report insolubility, intracellular retention, or absent secretion for Q368X: insoluble protein in HEK293T cells (PMID:11004290), absent secretion in COS-7 and human trabecular meshwork cells (PMID:16466712), and insoluble intracellularly retained protein in TM-1 cells (PMID:26396484). No OddsPath value or complete control/replicate documentation is available, so the VCEP BS3 calibration rule cannot be evaluated; the observed assay direction does not support BS3.
Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates. ... Applies to variants showing solubility or secretion in functional assays for studies with OddsPath \<0.48 as per the SVI recommendations.
The MYOC VCEP Version 2.1 CSPEC entry marks PVS1 as Not Applicable. Although this is a nonsense variant, the VCEP-specific applicability designation governs this assessment.
Not Applicable
The MYOC VCEP marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables entry for MYOC is empty, and no VCEP-approved PM1 domain or hotspot route is available for this variant.
Not Applicable
The MYOC VCEP marks PM3 as not applicable because MYOC variants have an autosomal dominant mode of inheritance; therefore phase with a pathogenic variant in trans and affected-proband observations cannot activate PM3 under this framework.
MYOC variants have an autosomal dominant mode of inheritance.
The variant consequence is nonsense, p.(Gln368Ter), rather than a missense substitution. The MYOC VCEP PM5 specification is the classic same-residue comparator rule for missense variants; therefore PM5 is not applicable to this stop-gain variant.
Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)
The MYOC VCEP marks PM6 as not applicable and directs users to PS2; it combines confirmed and assumed de novo evidence under PS2. PM6 is therefore not independently applied.
Refer to PS2
The MYOC VCEP explicitly marks PP2 as Not Applicable. No alternate generic missense-mechanism rule is permitted under the governing VCEP-only framework.
Not Applicable
The VCEP PP3 rule is a REVEL-based missense-prediction rule. NM_000261.2:c.1102C>T is a nonsense variant, p.(Gln368Ter), so PP3 is outside the applicable variant situation; the available BayesDel score is not named by this governing rule and is not used.
REVEL score of ≥ 0.932 ... REVEL score of 0.773-0.931 ... REVEL score of 0.644-0.772
The MYOC VCEP marks PP4 not applicable because the phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.
The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.
The governing VCEP explicitly exempts p.Gln368Ter from BS1. The variant is NP_000252.1:p.(Gln368Ter), so BS1 is not applicable regardless of its population frequency.
Allele frequency ≥ 0.001 in population databases. ... Does not apply to p.Gln368Ter.
The governing VCEP marks BS2 not applicable because MYOC variants have incomplete penetrance and late age of onset; therefore observation in a healthy adult cannot be used for this criterion in this framework.
MYOC variants have an incomplete penetrance and late age of onset.
The MYOC VCEP marks BS4 not applicable because phenocopies, reduced age-related penetrance, and the possibility of more than one pathogenic variant make non-segregation difficult to assess in MYOC-associated POAG. BS4 is therefore not applied.
The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG.
The MYOC VCEP explicitly marks BP1 as Not Applicable. No alternate generic benign missense rule is permitted under the governing VCEP-only framework.
Not Applicable
The MYOC VCEP marks BP2 as not applicable. Its specification notes that biallelic variants can occur and that cis effects may be possible, but it does not authorize BP2 for MYOC; therefore no cis/trans observation can activate BP2.
Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted.
The MYOC VCEP Version 2.1 CSPEC entry marks BP3 as Not Applicable. The variant's nonsense consequence and truncation therefore do not create a BP3 assessment under this governing framework.
Not Applicable
BP4 does not apply to a nonsense variant: a prediction of no splice impact leaves the truncating protein effect in place, so it is not evidence of no impact on the gene product. (Pipeline consistency rule; the criterion agent had marked BP4 met: Met at supporting strength: SpliceAI maximum delta 0.015 is below the VCEP’s ≤0.1 threshold for noncanonical variants without a splicing assay.)
* For missense variants: REVEL score of 0.184-0.290 * For all other variants located outside of donor/acceptor ±1,2 dinucleotide positions, when splicing assay is not available: SpliceAI ≤ 0.1
The MYOC VCEP marks BP5 not applicable because multiple molecular diagnoses are possible and variants in different genes could have an additive effect.
Multiple molecular diagnoses are possible and variants in different genes could have an additive effect.
The MYOC VCEP explicitly states that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule is limited to intronic/noncoding and synonymous silent exonic variants when BP4 is met. NM_000261.2:c.1102C>T is a nonsense exonic variant, so it lies outside BP7's stated scope regardless of the BP4 result.
Apply to intronic/noncoding and synonymous (silent) exonic variants if BP4 is met
Every interpreted variant in MYOC, mapped onto the exon structure of NM_000261.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)211 / 64,018 | 0.0033 |
| European (non-Finnish)1573 / 1,180,008 | 0.00131 hom |
| Remaining individuals40 / 62,500 | 0.00064 |
| African/African American22 / 74,984 | 0.00029 |
| Admixed American12 / 60,000 | 0.0002 |
| South Asian12 / 91,066 | 0.00013 |
| European (Finnish)84 / 25,118 | 0.0033 |
| European (non-Finnish)205 / 129,124 | 0.0016 |
| Remaining individuals6 / 7,222 | 0.00083 |
| African/African American7 / 24,938 | 0.00028 |
| South Asian6 / 30,612 | 0.0002 |
| Admixed American6 / 35,434 | 0.00017 |
This variant is present in gnomAD v4.1 (AF= 0.00115863; MAF= 0.11586%, 1870/1613974 alleles, homozygotes = 1) and has highest observed frequency in the European (Finnish) population (AF= 0.00329595; MAF= 0.32959%, 211/64018 alleles, homozygotes = 0); grpmax FAF= 0.00127788.
This variant is present in gnomAD v2.1 (AF= 0.00111047; MAF= 0.11105%, 314/282762 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00334422; MAF= 0.33442%, 84/25118 alleles, homozygotes = 0); grpmax FAF= 0.00139395.
Not available in gnomAD-Canada v1.0.
The VCEP PP3 rule is a REVEL-based missense-prediction rule. NM_000261.2:c.1102C>T is a nonsense variant, p.(Gln368Ter), so PP3 is outside the applicable variant situation; the available BayesDel score is not named by this governing rule and is not used.
REVEL score of ≥ 0.932 ... REVEL score of 0.773-0.931 ... REVEL score of 0.644-0.772
BP4 does not apply to a nonsense variant: a prediction of no splice impact leaves the truncating protein effect in place, so it is not evidence of no impact on the gene product. (Pipeline consistency rule; the criterion agent had marked BP4 met: Met at supporting strength: SpliceAI maximum delta 0.015 is below the VCEP’s ≤0.1 threshold for noncanonical variants without a splicing assay.)
* For missense variants: REVEL score of 0.184-0.290 * For all other variants located outside of donor/acceptor ±1,2 dinucleotide positions, when splicing assay is not available: SpliceAI ≤ 0.1
The VCEP BP7 rule is limited to intronic/noncoding and synonymous silent exonic variants when BP4 is met. NM_000261.2:c.1102C>T is a nonsense exonic variant, so it lies outside BP7's stated scope regardless of the BP4 result.
Apply to intronic/noncoding and synonymous (silent) exonic variants if BP4 is met
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.61701.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Premature truncation.
Table 1; Table 3; Results, paragraphs 3-5; Figure 2
In total, 29 Gln368STOP mutation carriers with POAG or OHT have been studied in detail (Table 1).
Results, paragraph beginning ‘In total, 29 Gln368STOP mutation carriers’; Penetrance subsection
five times the same disease-causing mutation (Q368X) in five unrelated POAG patients
Abstract; Results; Table 2, Patients 1-5; Discussion
In one large family, nine affected and ten unaffected individuals were identified with the Q368STOP mutation.
Abstract
Among these non-secreted variants, we recognized the Q368X mutant associated with about 1.5% of POAG patients
Results, section 3.1, paragraph 4; section 3.2, paragraph 3; Table 2
The protein products of both mutants are insoluble. When expressed in cultured cells, the proteins produced by both mutants are retained within the cell.
Results, “Transient expression of MYOC mutants”; Results, “Inducible expression of MYOC mutants in stable cell lines”; Discussion
A nonsense mutation (glutamine to stop) at codon 361
Results, mutation description; Table 1; Fig. 4 and accompanying text
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00115863; MAF= 0.11586%, 1870/1613974 alleles, homozygotes = 1) and has highest observed frequency in the European (Finnish) population (AF= 0.00329595; MAF= 0.32959%, 211/64018 alleles, homozygotes = 0); grpmax FAF= 0.00127788.
This variant is present in gnomAD v2.1 (AF= 0.00111047; MAF= 0.11105%, 314/282762 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00334422; MAF= 0.33442%, 84/25118 alleles, homozygotes = 0); grpmax FAF= 0.00139395.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Pathogenic by ClinGen Glaucoma Variant Curation Expert Panel (expert panel). (ClinVarID = 7949)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.61701.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50674786, n = 4 times).
This variant does not lie in a statistically significant hotspot.