About SMO
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMO c.1604G>T, p.(Trp535Leu)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
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.
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
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. 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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
Well-established functional studies demonstrate that W535L is a constitutively active gain-of-function variant in SMO. In Smo−/− MEFs, W535L drives Hedgehog pathway activation (GLI1 reporter) in the absence of ligand, confers strong resistance to the SMO inhibitor vismodegib (IC50 >320 nM vs wildtype IC50 ~8 nM), and provides a selective growth advantage to tumor cells under vismodegib treatment. W535L was originally identified as an activating mutation in sporadic BCCs (Xie et al. 1998) and confirmed in multiple independent studies. At the structural level, W535 is a conserved tryptophan (7.55) in helix VII critical for maintaining SMO autoinhibition; its mutation disrupts this regulatory mechanism. Functional evidence is robust and replicated across independent laboratories, but all studies are in somatic/cancer models; germline functional data are not available.
PM1Moderate
PM1 · moderate
W535 is located in a statistically significant mutational hotspot (Cancer Hotspots) within a critical functional domain. It resides in transmembrane helix VII at position 7.55, a conserved tryptophan essential for SMO autoinhibition. Mutation of this residue is shown to produce constitutive receptor activation (Wang et al. 2013). No benign variation is observed at this residue in population databases.
PM2Supporting
PM2 · supporting
NM_005631.4:c.1604G>T is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0 (genomes). Allele frequency in all populations is 0.0%, well below the 0.1% PM2 threshold for non-VCEP assessment.
PP3Supporting
PP3 · supporting
REVEL predicts a strongly deleterious effect (score 0.922). BayesDel score (0.463) is borderline. SpliceAI predicts no splice impact (max delta 0.00), consistent with a purely missense effect. The high REVEL score provides in silico support for pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PP3 supporting; combination = 2 moderate + 2 supporting, which maps to Likely Pathogenic.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
36 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV50824509, n = 36 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 4 met · 16 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005631.4:c.1604G>T (p.Trp535Leu) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0.0%.
W535L is a well-established constitutively active gain-of-function variant in SMO, demonstrated in Smo−/− MEFs to activate Hedgehog signaling (GLI1 reporter) in the absence of ligand and to confer strong resistance to the SMO inhibitor vismodegib (IC50 >320 nM vs wildtype ~8 nM).
W535 is located at position 7.55 in transmembrane helix VII, a conserved tryptophan residue critical for maintaining SMO autoinhibition. Structural studies confirm that mutation of this residue disrupts the inactive receptor conformation, producing constitutive activation.
W535L lies within a statistically significant mutational hotspot and no benign variation is observed at this residue in population databases.
REVEL in silico prediction score of 0.922 strongly supports a deleterious effect.
Applying generic ACMG/AMP 2015 final classification combination rules (PMID:25741868): Two moderate criteria (PS3, PM1) plus two supporting criteria (PM2, PP3) meet the threshold for Likely Pathogenic.
No criteria match.
Met · 4
PS3 ModerateWell-established functional studies demonstrate that W535L is a constitutively active gain-of-function variant in SMO. In Smo−/− MEFs, W535L drives Hedgehog pathway activation (GLI1 reporter) in the absence of ligand, confers strong resistance to the SMO inhibitor vismodegib (IC50 >320 nM vs wildtype IC50 ~8 nM), and provides a selective growth advantage to tumor cells under vismodegib treatment. W535L was originally identified as an activating mutation in sporadic BCCs (Xie et al. 1998) and confirmed in multiple independent studies. At the structural level, W535 is a conserved tryptophan (7.55) in helix VII critical for maintaining SMO autoinhibition; its mutation disrupts this regulatory mechanism. Functional evidence is robust and replicated across independent laboratories, but all studies are in somatic/cancer models; germline functional data are not available. Details ▾Hide ▴
Evidence considered
- W535L is constitutively active in Smo−/− MEFs
- activating GLI1 reporter in absence of SHH ligand (Atwood et al. 2015)
- W535L confers vismodegib resistance with IC50 >320 nM (Atwood et al. 2015)
- W535L provides selective growth advantage under vismodegib treatment in BCC competition assays (Atwood et al. 2015)
- W535L was originally discovered as an activating SMO mutation in sporadic BCCs (Xie et al. 1998)
- W535 is a structurally critical residue (7.55) for SMO autoinhibition
- mutation leads to constitutive activation (Wang et al. 2013)
Still missing
- Functional studies are in somatic/cancer context
- no germline-specific functional assays available
- Gain-of-function mechanism demonstrated in cancer models
- relevance to germline SMO-related disorders requires clinical correlation
Sources
PM1 ModerateW535 is located in a statistically significant mutational hotspot (Cancer Hotspots) within a critical functional domain. It resides in transmembrane helix VII at position 7.55, a conserved tryptophan essential for SMO autoinhibition. Mutation of this residue is shown to produce constitutive receptor activation (Wang et al. 2013). No benign variation is observed at this residue in population databases. Details ▾Hide ▴
Evidence considered
- W535 is a statistically significant hotspot residue (Cancer Hotspots)
- W535 (7.55) is a structurally critical residue for SMO autoinhibition
- mutation leads to constitutive activation (Wang et al. 2013)
- No benign variation at codon 535 in gnomAD
Still missing
- Hotspot designation is based on somatic cancer mutation data
- germline hotspot significance not established
Sources
PM2 SupportingNM_005631.4:c.1604G>T is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0 (genomes). Allele frequency in all populations is 0.0%, well below the 0.1% PM2 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = null
- AC = null)
- Absent from gnomAD v4.1 (AF = null
- Absent from gnomAD-Canada v1.0 (AF = 0.0)
Sources
PP3 SupportingREVEL predicts a strongly deleterious effect (score 0.922). BayesDel score (0.463) is borderline. SpliceAI predicts no splice impact (max delta 0.00), consistent with a purely missense effect. The high REVEL score provides in silico support for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score 0.922 (strongly pathogenic prediction)
- BayesDel score 0.463 (borderline)
- SpliceAI max delta 0.00 (no splice impact)
Sources
Not met · 16 · evaluated, threshold not reached
PS1 No prior pathogenic variant at codon 535 with a different nucleotide change producing the same amino acid (Trp535Leu) has been identified. No other pathogenic missense change at this codon is reported in ClinVar. Details ▾Hide ▴
Evidence considered
- No same-codon pathogenic comparator variants identified in ClinVar or literature
Sources
PS4 No germline case-control data demonstrating statistically significant enrichment of W535L in affected individuals versus population controls. All reported observations are somatic: 36 occurrences in COSMIC, 3/30 resistant BCCs and 1/36 untreated BCCs (Atwood et al. 2015), and original discovery in sporadic BCCs (Xie et al. 1998). Somatic prevalence data do not satisfy PS4 for germline variant interpretation. Details ▾Hide ▴
Evidence considered
- Somatic observations only (COSMIC n=36
- Atwood 2015 BCC cohort
- Xie 1998 original report)
- No germline case-control data available
Still missing
- No germline case-control or cohort enrichment data
Sources
PP1 No cosegregation data are available for this variant. No family studies with multiple affected members have been reported. Details ▾Hide ▴
Evidence considered
- No cosegregation or family data available
Still missing
- No family segregation data
PP2 Insufficient evidence to establish that SMO has a low rate of benign missense variation. The HCI prior score is not available for SMO. While missense gain-of-function variants are a recognized mechanism in SMO, gene-level missense constraint metrics are not established. Details ▾Hide ▴
Evidence considered
- HCI prior not available for SMO (gene not supported)
- No established gene-level missense constraint data
Still missing
- No gene-level missense constraint metric (HCI prior
- Z-score
- pLI for missense)
PP4 No patient phenotype or family history information is available for this variant assessment. The variant was submitted to ClinVar by OMIM in a somatic BCC context without detailed clinical information. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available
Still missing
- No proband phenotype or clinical history provided
PP5 The single ClinVar submission (OMIM, SCV000028794) classifies the variant as Pathogenic but with review status 'no assertion criteria provided' in a somatic context. This does not satisfy PP5 requirements for a reputable germline source with supporting evidence. No CSPEC/VCEP classification exists for SMO. Details ▾Hide ▴
Evidence considered
- ClinVar OMIM submission: Pathogenic
- somatic
- no assertion criteria — does not qualify as reputable germline source
Sources
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0.0%, far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all gnomAD populations
Sources
BS1 The variant is absent from gnomAD. Allele frequency is 0.0%, far below the 0.3% BS1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all gnomAD populations
Sources
BS2 The variant is absent from population databases, providing no evidence of observation in healthy adults. No healthy adult carriers have been reported. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no healthy adult carriers identified
Sources
BS3 Well-established functional studies demonstrate the OPPOSITE of a benign effect: W535L is a constitutively active gain-of-function variant that drives Hedgehog pathway activation in the absence of ligand and confers strong resistance to SMO inhibitors. These findings are incompatible with a benign functional interpretation. Details ▾Hide ▴
Evidence considered
- Functional studies consistently show gain-of-function
- not neutral effect
- W535L is constitutively active
- not benign
Sources
BS4 No cosegregation data are available to assess lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No family segregation or cosegregation studies
BP1 Missense gain-of-function variants are a recognized disease mechanism for SMO. W535L is a well-characterized activating mutation, and the SMO gene is not limited to a truncating-only disease mechanism. Details ▾Hide ▴
Evidence considered
- Missense gain-of-function is a known disease mechanism for SMO
- W535L is a constitutively active missense variant
Sources
BP2 No phasing data are available to assess whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans or cis phasing data available
Still missing
- No phasing or allelic data
BP4 REVEL score of 0.922 strongly predicts a deleterious effect, contradicting BP4 requirements for multiple lines of computational evidence suggesting no impact. SpliceAI predicts no splice effect (max delta 0.00) but this alone is insufficient when REVEL strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.922 — strongly deleterious prediction
- incompatible with BP4
Sources
BP5 No data available to demonstrate that this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No alternate molecular diagnosis data for probands carrying this variant
BP6 No reputable source has reported this variant as benign. The single ClinVar submission classifies it as Pathogenic (somatic). Details ▾Hide ▴
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005631.4:c.1604G>T is a missense variant (p.Trp535Leu). It does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS2 N/ANo de novo occurrence data (with confirmed maternity and paternity) available for this variant. The single ClinVar submission (OMIM, SCV000028794) is derived from literature only in a somatic context. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No germline segregation or de novo testing data available
Sources
PM5 N/ANo alternative pathogenic missense variant at codon 535 has been identified in ClinVar or published literature. PM5 candidate harvesting returned zero same-residue comparator variants. The PM5 criterion cannot be applied without a confirmed pathogenic comparator at the same residue. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidate variants identified in ClinVar or literature
Sources
pm5_candidatesclinvar ↗
PM6 N/ANo de novo observation (assumed or confirmed) of W535L has been reported in a germline context. All reported occurrences are somatic. Details ▾Hide ▴
Evidence considered
- No de novo germline reports available
Still missing
- No germline de novo testing data
BP3 N/AThe variant is a single-nucleotide substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_005631.4:c.1604G>T is a missense variant (p.Trp535Leu), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
PS5 N/ANo reputable germline source has recently reported this variant as pathogenic with unavailable evidence. The single ClinVar submission (OMIM, SCV000028794) classifies as Pathogenic in a somatic context with no assertion criteria provided and does not constitute a reputable germline source. Details ▾Hide ▴
Evidence considered
- ClinVar OMIM submission: somatic Pathogenic
- no assertion criteria
- not a reputable germline source
Sources
Identifiers
- Gene
- SMO
- Transcript
- NM_005631.4
- Coding (HGVS c.)
- NM_005631.4:c.1604G>T
- Protein (HGVS p.)
- NP_005622.1:p.(Trp535Leu)
- GRCh38
- chr7:129210500 G>T
- GRCh37
- chr7:128850341 G>T
- ClinVar
- 8117
- COSMIC
- COSV50824509
Gene diagram
Every interpreted variant in SMO, mapped onto the exon structure of NM_005631.4. Select a row to find it on the plot.
SMONM_005631.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SMO
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.922
- BayesDel
- 0.463
How the predictions were used
PP3 SupportingREVEL predicts a strongly deleterious effect (score 0.922). BayesDel score (0.463) is borderline. SpliceAI predicts no splice impact (max delta 0.00), consistent with a purely missense effect. The high REVEL score provides in silico support for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score 0.922 (strongly pathogenic prediction)
- BayesDel score 0.463 (borderline)
- SpliceAI max delta 0.00 (no splice impact)
Sources
BP4 REVEL score of 0.922 strongly predicts a deleterious effect, contradicting BP4 requirements for multiple lines of computational evidence suggesting no impact. SpliceAI predicts no splice effect (max delta 0.00) but this alone is insufficient when REVEL strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.922 — strongly deleterious prediction
- incompatible with BP4
Sources
BP7 N/ANM_005631.4:c.1604G>T is a missense variant (p.Trp535Leu), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.922. BayesDel score = 0.462622.
3 paper records listed. 3 cited in the classification.
Cited in the classification
-
PMID 23636324 ↗Structure of the human smoothened receptor bound to an antitumour agent.Crystal structure of the human SMO receptor 7TM domain at 2.5 Å resolution reveals that W535, located at position 7.55 in helix VII, is a conserved tryptophan critical for receptor autoinhibition. The paper notes that mutation of W535 leads to a constitutively active SMO receptor, providing structural basis for the gain-of-function effect.→ PS3 → PM1 Names this variant
Source detail
W535 7.55 in helix VII. The latter tryptophan, conserved among class F and superimposable with the location of the NPxxY motif of class A, is shown to play an important role in receptor activation, as mutation of W535 7.55 leads to a constitutively active SMO receptor.
Location Results section: 'Homology with Frizzled family receptors'; Figure 6
Context X-ray crystallography of human SMO 7TM domain bound to LY2940680 antagonist; structural analysis
-
PMID 25759020 ↗Smoothened variants explain the majority of drug resistance in basal cell carcinoma.W535L identified in 3/30 vismodegib-resistant BCCs and 1/36 untreated BCCs. Functional characterization in Smo−/− MEFs demonstrated W535L is constitutively active (GLI1 reporter activation without SHH ligand), confers high-level vismodegib resistance (IC50 >320 nM vs wildtype ~8 nM), and provides a selective growth advantage under drug treatment. In paired pre/post-treatment biopsies, W535L subclones present at low allele fraction before treatment were enriched during therapy, confirming its role in acquired resistance.→ PS3 Names this variant
Source detail
W535L in another three resistant BCCs. Also known as SMO-M2, W535L is a known oncogenic mutation present at low rates in sporadic BCCs and can drive tumor progression in the absence of PTCH1 loss.
Location Results: 'Exome sequencing identifies recurrent SMO mutations in resistant BCC'; Figure 2B, 2E, 4A-F, 5A
Context Smo−/− mouse embryonic fibroblasts (MEFs), GLI-luciferase reporter assays, ASZ001 BCC cell line competition assays (mCherry/GFP), patient-derived BCC sequencing
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PMID 9422511 ↗Activating Smoothened mutations in sporadic basal-cell carcinoma.Xie J et al. · 1998 Jan 1Original identification of W535L (SMO-M2) as a constitutively active Smoothened mutation in sporadic basal cell carcinomas. W535L was shown to activate Hedgehog signaling in the absence of PTCH1 loss and contribute to BCC tumorigenesis.→ PS3 Names this variant
Source detail
W535L is a known oncogenic mutation present at low rates in sporadic BCCs and can drive tumor progression in the absence of PTCH1 loss (Xie et al., 1998).
Location Confirmed via explicit citation in Atwood et al. 2015 (PMID:25759020), which states: 'Also known as SMO-M2, W535L is a known oncogenic mutation present at low rates in sporadic BCCs and can drive tumor progression in the absence of PTCH1 loss (Xie et al., 1998).'
Context Functional characterization in cell-based Hedgehog signaling assays
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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 ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/8117/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-128850341-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-129210500-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-129210500-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005631.4%3Ac.1604…
- OncoKB ↗www.oncokb.org/gene/SMO/W535L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122821025
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is present in ClinVar (Variation ID: 8117); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.922. BayesDel score = 0.462622.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50824509, n = 36 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.