About MYOC
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYOC c.719A>G, p.(Glu240Gly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
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.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000261.2:c.719A>G is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF = 3.72e-06, 6/1,614,146 alleles, 0 homozygotes; grpmax FAF = 1.83e-06). This meets the Glaucoma VCEP PM2 threshold of allele frequency ≤ 0.0001 (0.01%) at supporting strength.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
BP4 is met at supporting strength per the Glaucoma VCEP v2.1. The REVEL score for NM_000261.2:c.719A>G (p.Glu240Gly) is 0.205, falling within the supporting benign range of 0.184-0.290 for missense variants. Additionally, SpliceAI predicts no splice impact (max delta = 0.01, ≤0.1).
Recorded classification: Uncertain significance
ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.1 v2.1 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,614,146 alleles
gnomAD v4.1: 6 / 1,614,146 alleles. Recorded AF 3.71714e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: reviewed by expert panel.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MYOC VCEP v2.1, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 5 not met · 5 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000261.2:c.719A>G (p.Glu240Gly) in MYOC is a rare missense variant absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 3.72e-06, 6/1,614,146 alleles), meeting PM2 at supporting strength per the ClinGen Glaucoma VCEP v2.1.
The REVEL score of 0.205 falls within the VCEP BP4 supporting range (0.184-0.290), and SpliceAI predicts no splice impact (max delta = 0.01), meeting BP4 at supporting strength.
This variant has been reported in ClinVar as Uncertain Significance by the ClinGen Glaucoma Variant Curation Expert Panel (ClinVar ID 2442275, reviewed by expert panel).
No functional studies, de novo reports, proband counts, or segregation data were identified for this variant in the available literature. PS1, PS2, PS3, PS4, PP1, and BS3 remain not assessed due to absence of data.
Under the Glaucoma VCEP v2.1 point-based scoring system, the variant accumulates +1 point (PM2_supporting) and -1 point (BP4_supporting), yielding a total of 0 points, which falls within the Uncertain Significance range (-1 to 5 points).
No criteria match.
Met · 2
PM2 SupportingNM_000261.2:c.719A>G is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF = 3.72e-06, 6/1,614,146 alleles, 0 homozygotes; grpmax FAF = 1.83e-06). This meets the Glaucoma VCEP PM2 threshold of allele frequency ≤ 0.0001 (0.01%) at supporting strength. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: variant absent.
- gnomAD v4.1: AF = 3.72e-06 (6/1
- 614
- 146 alleles)
- highest in NFE (AF = 5.08e-06
- 6/1
- 180
- 006).
- Grpmax FAF = 1.83e-06
- well below PM2 threshold of 0.0001.
Sources
BP4 SupportingBP4 is met at supporting strength per the Glaucoma VCEP v2.1. The REVEL score for NM_000261.2:c.719A>G (p.Glu240Gly) is 0.205, falling within the supporting benign range of 0.184-0.290 for missense variants. Additionally, SpliceAI predicts no splice impact (max delta = 0.01, ≤0.1). Details ▾Hide ▴
Evidence considered
- REVEL score = 0.205 (BP4_supporting range: 0.184-0.290 for missense variants).
- SpliceAI max delta = 0.01 (≤0.1
- no predicted splice impact).
- BayesDel score = -0.343 (consistent with benign prediction).
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No previously established pathogenic or likely pathogenic variant with the same amino acid change (p.Glu240Gly) has been reported. This variant itself is classified as Uncertain Significance by the ClinGen Glaucoma VCEP (ClinVar ID 2442275). Details ▾Hide ▴
PM5 PM5 is not met for NM_000261.2:c.719A>G (p.Glu240Gly). The Glaucoma VCEP v2.1 requires both (a) a previously established pathogenic or likely pathogenic variant at the same residue (Glu240) assessed independently of PM5, and (b) the variant must meet PP3. No established P/LP variants exist at position 240. Additionally, PP3 is not met (REVEL = 0.205, below the supporting threshold of 0.644). Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates with P/LP classification.
- PP3 prerequisite not satisfied: REVEL = 0.205 (threshold ≥0.644 for PP3_supporting).
- SpliceAI max delta = 0.01 (≤0.2
- splicing prerequisite satisfied).
Sources
PP3 PP3 is not met for NM_000261.2:c.719A>G (p.Glu240Gly). The REVEL score is 0.205, which falls below the Glaucoma VCEP PP3 supporting threshold of 0.644. BayesDel score is -0.343, which is also in the benign range. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.205 (PP3_supporting threshold ≥0.644
- moderate ≥0.773
- strong ≥0.932).
- BayesDel score = -0.343 (negative
- consistent with benign prediction).
- SpliceAI max delta = 0.01 (no predicted splice impact).
- HCI prior: not available for MYOC.
Sources
BA1 BA1 is not met. The highest population allele frequency for NM_000261.2:c.719A>G is 5.08e-06 in the European (non-Finnish) population, far below the Glaucoma VCEP BA1 threshold of ≥0.01 (1%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 NFE AF = 5.08e-06 (highest subpopulation).
- Total AF = 3.72e-06
- well below BA1 threshold of 0.01.
Sources
BS1 BS1 is not met. The highest population allele frequency for NM_000261.2:c.719A>G is 5.08e-06, far below the Glaucoma VCEP BS1 threshold of ≥0.001 (0.1%). The variant is absent from gnomAD v2.1 and present only at extremely low frequency in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: AF = 3.72e-06
- highest subpopulation AF (NFE) = 5.08e-06.
- BS1 threshold: ≥0.001.
Sources
Not assessed · 5 · no assessment recorded
PS2 No de novo reports were identified for NM_000261.2:c.719A>G (p.Glu240Gly) in the literature. PS2 requires confirmed or assumed de novo occurrence in JOAG or POAG per the Glaucoma VCEP v2.1. Details ▾Hide ▴
Evidence considered
- No de novo data available for this variant.
Still missing
- No de novo studies identified
- parental testing data unavailable.
PS3 No functional assay data (solubility, secretion, or aggregation assays with OddsPath calculations) were identified for NM_000261.2:c.719A>G (p.Glu240Gly) in the literature. PS3 per the Glaucoma VCEP v2.1 requires well-established functional studies with OddsPath thresholds. Details ▾Hide ▴
Evidence considered
- No functional data available for this variant.
Still missing
- No in vitro or in vivo functional studies identified
- secretion/solubility assays not available.
PS4 No proband counts from independent studies were identified for NM_000261.2:c.719A>G (p.Glu240Gly). PS4 per the Glaucoma VCEP v2.1 requires at least 2 probands with JOAG or POAG from multiple independent studies for supporting-level evidence. Details ▾Hide ▴
Evidence considered
- ClinVar records a single expert panel submission (VUS) with no proband-level data.
Still missing
- No case reports or cohort studies with proband counts available.
Sources
PP1 No co-segregation data were identified for NM_000261.2:c.719A>G (p.Glu240Gly). PP1 per the Glaucoma VCEP v2.1 requires at least 3 informative meioses for supporting-level evidence. Details ▾Hide ▴
Evidence considered
- No family segregation studies available for this variant.
Still missing
- No family studies or segregation data identified.
BS3 No functional assay data demonstrating normal solubility or secretion were identified for NM_000261.2:c.719A>G (p.Glu240Gly). BS3 per the Glaucoma VCEP v2.1 requires functional studies with OddsPath <0.23 (moderate) or <0.48 (supporting). Details ▾Hide ▴
Evidence considered
- No functional benign data available for this variant.
Still missing
- No secretion or solubility assays identified for this variant.
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC disease mechanism is gain-of-function, not loss-of-function, and PVS1 is reserved for truncating variants via PM4 in this framework. NM_000261.2:c.719A>G is a missense variant (p.Glu240Gly). Details ▾Hide ▴
Evidence considered
- ClinGen Glaucoma VCEP v2.1 explicitly marks PVS1 as Not Applicable for this gene.
Sources
PM1 VCEPPM1 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC has no mutational hotspot and benign variants are present throughout the well-characterized olfactomedin domain in exon 3. Details ▾Hide ▴
Evidence considered
- VCEP states: 'MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3.'
Sources
PM6 VCEPPM6 is not applicable per the ClinGen Glaucoma VCEP v2.1. The VCEP directs users to refer to PS2 for de novo evidence instead. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable per the ClinGen Glaucoma VCEP v2.1. Although pathogenic missense variants are common in MYOC, the gene has a significant amount of benign missense variation (gnomAD missense constraint z = 0.52), supporting tolerance to variation. Details ▾Hide ▴
Evidence considered
- VCEP states: 'MYOC has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation.'
Sources
PP4 VCEPPP4 is not applicable per the ClinGen Glaucoma VCEP v2.1. The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity in glaucoma. Details ▾Hide ▴
Evidence considered
- VCEP states: 'The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.'
Sources
PP5 VCEPPP5 is not applicable per the ClinGen Glaucoma VCEP v2.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS2 VCEPBS2 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC variants have incomplete penetrance and late age of onset, making the observation of a variant in a healthy individual uninformative. Details ▾Hide ▴
Evidence considered
- VCEP states: 'MYOC variants have an incomplete penetrance and late age of onset.'
Sources
BS4 VCEPBS4 is not applicable per the ClinGen Glaucoma VCEP v2.1. Phenocopies, reduced age-related penetrance, and the possibility of multiple pathogenic variants make non-segregation difficult to assess in MYOC-associated glaucoma. Details ▾Hide ▴
Evidence considered
- VCEP states BS4 is not applicable due to phenocopies and reduced penetrance.
Sources
BP1 VCEPBP1 is not applicable per the ClinGen Glaucoma VCEP v2.1. Both truncating and missense MYOC variants are causative; the gene is not one for which primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- VCEP states: 'Both truncating and missense MYOC variants are causative.'
Sources
BP2 VCEPBP2 is not applicable per the ClinGen Glaucoma VCEP v2.1. Variants occurring in cis or trans are not reliably interpretable given variable phenotype and potential synergistic effects. Details ▾Hide ▴
Evidence considered
- VCEP states BP2 is not applicable: biallelic variants reported with variable phenotype.
Sources
BP5 VCEPBP5 is not applicable per the ClinGen Glaucoma VCEP v2.1. Multiple molecular diagnoses are possible in glaucoma and variants in different genes could have additive effects. Details ▾Hide ▴
Evidence considered
- VCEP states BP5 is not applicable: 'Multiple molecular diagnoses are possible and variants in different genes could have an additive effect.'
Sources
BP6 VCEPBP6 is not applicable per the ClinGen Glaucoma VCEP v2.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 is not applicable. NM_000261.2:c.719A>G is a missense variant (p.Glu240Gly), not an intronic, noncoding, or synonymous variant. The Glaucoma VCEP v2.1 restricts BP7 to intronic/noncoding and synonymous exonic variants that also meet BP4. Details ▾Hide ▴
Evidence considered
- BP7 applies only to intronic/noncoding and synonymous variants
- c.719A>G is a missense substitution.
Sources
PS5 N/APS5 is not defined in the ClinGen Glaucoma VCEP v2.1 and is of the same class as PP5/BP6 (reputable source reports), which the VCEP explicitly marks as Not Applicable per ClinGen SVI VCEP Review Committee recommendations. Details ▾Hide ▴
Evidence considered
- PS5 is absent from the MYOC VCEP criteria set
- PP5 and BP6 are explicitly Not Applicable for this VCEP.
Sources
Identifiers
- Gene
- MYOC
- Transcript
- NM_000261.2
- Coding (HGVS c.)
- NM_000261.2:c.719A>G
- Protein (HGVS p.)
- NP_000252.1:p.(Glu240Gly)
- GRCh38
- chr1:171638608 T>C
- GRCh37
- chr1:171607748 T>C
- ClinVar
- 2442275
Gene diagram
Every interpreted variant in MYOC, mapped onto the exon structure of NM_000261.2. Select a row to find it on the plot.
MYOCNM_000261.2
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MYOC
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
6 / 1,614,146 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,614,146 alleles · 0 hom · FAF 1.8e-06
| European (non-Finnish)6 / 1,180,006 | 5.1e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71714e-06; MAF= 0.00037%, 6/1614146 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08472e-06; MAF= 0.00051%, 6/1180006 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.205
- BayesDel
- -0.343
How the predictions were used
BP4 SupportingBP4 is met at supporting strength per the Glaucoma VCEP v2.1. The REVEL score for NM_000261.2:c.719A>G (p.Glu240Gly) is 0.205, falling within the supporting benign range of 0.184-0.290 for missense variants. Additionally, SpliceAI predicts no splice impact (max delta = 0.01, ≤0.1). Details ▾Hide ▴
Evidence considered
- REVEL score = 0.205 (BP4_supporting range: 0.184-0.290 for missense variants).
- SpliceAI max delta = 0.01 (≤0.1
- no predicted splice impact).
- BayesDel score = -0.343 (consistent with benign prediction).
Sources
PP3 PP3 is not met for NM_000261.2:c.719A>G (p.Glu240Gly). The REVEL score is 0.205, which falls below the Glaucoma VCEP PP3 supporting threshold of 0.644. BayesDel score is -0.343, which is also in the benign range. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.205 (PP3_supporting threshold ≥0.644
- moderate ≥0.773
- strong ≥0.932).
- BayesDel score = -0.343 (negative
- consistent with benign prediction).
- SpliceAI max delta = 0.01 (no predicted splice impact).
- HCI prior: not available for MYOC.
Sources
BP7 N/ABP7 is not applicable. NM_000261.2:c.719A>G is a missense variant (p.Glu240Gly), not an intronic, noncoding, or synonymous variant. The Glaucoma VCEP v2.1 restricts BP7 to intronic/noncoding and synonymous exonic variants that also meet BP4. Details ▾Hide ▴
Evidence considered
- BP7 applies only to intronic/noncoding and synonymous variants
- c.719A>G is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.205. BayesDel score = -0.343469.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,614,146 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/635003679
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2442275/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-171607748-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-171638608-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-171638608-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000261.2%3Ac.719A…
- OncoKB ↗www.oncokb.org/gene/MYOC/E240G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MYOC+c.719A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71714e-06; MAF= 0.00037%, 6/1614146 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08472e-06; MAF= 0.00051%, 6/1180006 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain Significance by ClinGen Glaucoma Variant Curation Expert Panel (expert panel). (ClinVarID = 2442275)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.205. BayesDel score = -0.343469.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.