About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.1474G>A, p.(Glu492Lys)
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: 5
Benign evidence criteria: 1
Pathogenic criteria applied · 5
PS3Moderate
PS3 · moderate
Functional characterization of NTRK1 E492K in patient-derived iPSC neural stem cells demonstrated significantly reduced neurite outgrowth upon NGF treatment and markedly reduced NTRK1 gene expression compared to control cells. A conditional E495K (mouse ortholog) knock-in mouse model was generated and exhibited altered hippocampal pERK signaling, supporting a functional consequence of this variant on TrkA signaling.
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in population databases: gnomAD v2.1 AF = 0.044% (124/282,262 alleles, 0 homozygotes); gnomAD v4.1 AF = 0.069% (1,113/1,613,264 alleles, 1 homozygote). Highest subpopulation frequency is 0.089% (NFE, gnomAD v4.1). Allele frequency is below the 0.1% threshold for PM2 at supporting strength. The single homozygote in v4.1 is noted but does not negate PM2 at supporting level for a recessive condition.
PP1Supporting
PP1 · supporting
The NTRK1 E492K variant co-segregates with disease in a large multiplex pedigree (family 6807) in which seven members had both autosomal dominant tubulointerstitial kidney disease (ADTKD) and mood disorders including five with bipolar disorder (PMID:33235206). Perfect co-segregation of the variant with ADTKD and mood disorders was observed in this family.
PP3Supporting
PP3 · supporting
In silico prediction tools support a deleterious effect: REVEL score 0.757 (damaging threshold >0.5); PolyPhen-2 score 0.99 (probably damaging) reported in PMID:33235206. BayesDel score 0.297 is discordant but REVEL is the verified predictor in this pipeline. SpliceAI max delta 0.08 indicates no splicing impact.
PP4Supporting
PP4 · supporting
The homozygous p.Glu492Lys variant was identified in a patient with a congenital syndrome of sensory neuropathy, anhidrosis, seizures, deafness, and developmental delay (PMID:24154508, citing Davidson et al. 2012 PMID:22302274). This phenotype constellation is highly specific for congenital insensitivity to pain with anhidrosis (CIPA/HSAN4), which is exclusively caused by biallelic NTRK1 mutations.
Benign criteria applied · 1
BS2Supporting
BS2 · supporting
One homozygous individual for NM_002529.3:c.1474G>A (p.Glu492Lys) is present in gnomAD v4.1 (1 homozygote among 1,613,264 alleles). For a fully penetrant autosomal recessive condition (CIPA/HSAN4) that presents at birth with severe sensory and autonomic dysfunction, observation of a presumed healthy adult homozygote in a population database that excludes severe pediatric disease argues against complete penetrance. However, the phenotype of this individual is unknown, and the variant may be hypomorphic.
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, PM2 supporting, PP1 supporting, PP3 supporting, PP4 supporting, BS2 supporting benign; combination = 1 moderate + 4 supporting + 1 supporting benign, 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
1,113 / 1,613,264 alleles
gnomAD v4.1: 1,113 / 1,613,264 alleles. Recorded AF 0.000689906. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000439308; MAF= 0.04393%, 124/282262 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000814105; MAF= 0.08141%, 105/128976 alleles, homozygotes = 0); grpmax FAF= 0.00070845.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.080 maximum delta
Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
8 reported laboratory submissions
6 Uncertain significance · 1 Uncertain Significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.
COSMIC
Cancer Hotspots
Somatic evidence
7 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62324977, n = 7 times).
Cancer Hotspots
This variant does not lie 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.
26 criteria with recorded statuses: 6 met · 17 not met · 1 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NTRK1 c.1474G>A (p.Glu492Lys) has been reported as a homozygous variant in a patient with congenital sensory neuropathy, anhidrosis, seizures, deafness, and developmental delay, a phenotype consistent with congenital insensitivity to pain with anhidrosis (CIPA/HSAN4), which is exclusively caused by biallelic NTRK1 mutations.
Functional characterization of NTRK1 E492K in patient-derived iPSC neural stem cells demonstrated significantly reduced neurite outgrowth upon NGF treatment and markedly reduced NTRK1 gene expression compared to control cells; a conditional knock-in mouse model recapitulated altered TrkA signaling.
The variant co-segregates with disease in a multiplex family in which seven members had both ADTKD and mood disorders including five with bipolar disorder, providing evidence of co-segregation though with a phenotype that differs from classic NTRK1-related CIPA.
The variant is present at low frequency in population databases: gnomAD v2.1 allele frequency 0.044% (124/282,262 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 0.069% (1,113/1,613,264 alleles, 1 homozygote), meeting PM2 at supporting level.
In silico predictions support a deleterious effect: REVEL score 0.757 (damaging), PolyPhen-2 score 0.99 (probably damaging); SpliceAI max delta 0.08 indicates no splicing impact.
One homozygous individual is observed in gnomAD v4.1, which for a fully penetrant severe autosomal recessive condition presenting at birth argues against complete penetrance; however, the phenotype of this individual is unknown and the variant may be hypomorphic.
ClinVar classification is Uncertain Significance (Variation ID 418887, 7 submissions) with one Likely benign submission; no expert panel review exists.
Overall balance of evidence: one moderate pathogenic criterion (PS3), four supporting pathogenic criteria (PM2, PP1, PP3, PP4), and one supporting benign criterion (BS2). This yields a net classification of Uncertain Significance per ACMG/AMP 2015 combination rules.
No criteria match.
Met · 6
PS3 ModerateFunctional characterization of NTRK1 E492K in patient-derived iPSC neural stem cells demonstrated significantly reduced neurite outgrowth upon NGF treatment and markedly reduced NTRK1 gene expression compared to control cells. A conditional E495K (mouse ortholog) knock-in mouse model was generated and exhibited altered hippocampal pERK signaling, supporting a functional consequence of this variant on TrkA signaling. Details ▾Hide ▴
Evidence considered
- Patient iPSC-derived NSCs with E492K showed reduced neurite growth (Fig. 2c).
- E492K NSC line had low/ablated NTRK1 expression by qPCR (Fig. 2d).
- Conditional knock-in mouse (E495K) generated
- altered pERK in hippocampus.
- PolyPhen-2 predicted damaging with score 0.99.
Still missing
- Single study
- a second independent functional study would strengthen this criterion to strong.
Sources
PM2 SupportingThis variant is present at very low frequency in population databases: gnomAD v2.1 AF = 0.044% (124/282,262 alleles, 0 homozygotes); gnomAD v4.1 AF = 0.069% (1,113/1,613,264 alleles, 1 homozygote). Highest subpopulation frequency is 0.089% (NFE, gnomAD v4.1). Allele frequency is below the 0.1% threshold for PM2 at supporting strength. The single homozygote in v4.1 is noted but does not negate PM2 at supporting level for a recessive condition. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.044%
- 124/282
- 262 alleles
- 0 homozygotes.
- gnomAD v4.1: AF = 0.069%
- 1
- 113/1
- 613
- 264 alleles
- 1 homozygote.
- grpmax FAF = 0.000845 (v4.1).
- Highest subpopulation: NFE AF = 0.089% (v4.1).
Sources
PP1 SupportingThe NTRK1 E492K variant co-segregates with disease in a large multiplex pedigree (family 6807) in which seven members had both autosomal dominant tubulointerstitial kidney disease (ADTKD) and mood disorders including five with bipolar disorder (PMID:33235206). Perfect co-segregation of the variant with ADTKD and mood disorders was observed in this family. Details ▾Hide ▴
Evidence considered
- E492K co-segregates with ADTKD and mood disorders in a large multiplex pedigree (7 affected members across generations
- Fig. 1a).
- Linkage analysis: LOD score of 1.6 at chromosome 1q22 encompassing NTRK1.
Still missing
- Co-segregation is with a phenotype (BD + ADTKD) not classic CIPA/HSAN4
- clinical relevance to NTRK1-related CIPA is indirect.
Sources
PP3 SupportingIn silico prediction tools support a deleterious effect: REVEL score 0.757 (damaging threshold >0.5); PolyPhen-2 score 0.99 (probably damaging) reported in PMID:33235206. BayesDel score 0.297 is discordant but REVEL is the verified predictor in this pipeline. SpliceAI max delta 0.08 indicates no splicing impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.757 (damaging).
- PolyPhen-2: 0.99 (probably damaging).
- BayesDel: 0.297 (discordant
- below damaging threshold).
- SpliceAI max delta: 0.08 (no splicing impact).
Sources
PP4 SupportingThe homozygous p.Glu492Lys variant was identified in a patient with a congenital syndrome of sensory neuropathy, anhidrosis, seizures, deafness, and developmental delay (PMID:24154508, citing Davidson et al. 2012 PMID:22302274). This phenotype constellation is highly specific for congenital insensitivity to pain with anhidrosis (CIPA/HSAN4), which is exclusively caused by biallelic NTRK1 mutations. Details ▾Hide ▴
Evidence considered
- Homozygous p.Glu492Lys identified in a patient with sensory neuropathy
- anhidrosis
- seizures
- deafness
- and developmental delay.
- Phenotype is highly specific for CIPA/HSAN4 (NTRK1-associated).
Still missing
- Full text of primary paper PMID:22302274 (Davidson et al. 2012) was not available for direct review
- variant confirmation is through the review paper PMID:24154508.
Sources
BS2 SupportingOne homozygous individual for NM_002529.3:c.1474G>A (p.Glu492Lys) is present in gnomAD v4.1 (1 homozygote among 1,613,264 alleles). For a fully penetrant autosomal recessive condition (CIPA/HSAN4) that presents at birth with severe sensory and autonomic dysfunction, observation of a presumed healthy adult homozygote in a population database that excludes severe pediatric disease argues against complete penetrance. However, the phenotype of this individual is unknown, and the variant may be hypomorphic. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 homozygous individual observed.
- CIPA/HSAN4 is a severe autosomal recessive condition presenting at birth
- gnomAD v4 excludes known severe pediatric disease.
Still missing
- Phenotype of the homozygous gnomAD individual is unknown
- cannot confirm healthy adult status.
- Variant may be hypomorphic
- pathogenic homozygous variants in CIPA genes have been reported in population databases at low frequency.
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No evidence was identified that a different nucleotide change at c.1474 resulting in the same amino acid substitution (p.Glu492Lys) has been previously classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at this position with established pathogenicity identified in ClinVar or literature.
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or reviewed literature.
PS4 No case-control data or statistically significant enrichment of this variant in affected individuals versus controls was identified. The variant has been observed in individual cases and one multiplex family but without formal statistical comparison. Details ▾Hide ▴
Evidence considered
- Variant reported in individual patients and one family but no case-control association data available.
Still missing
- Formal case-control studies or aggregate cohort data would be required.
PM1 Residue 492 is located in the juxtamembrane region of TrkA, near the SHC-binding phosphotyrosine site (Y490), but not within a statistically significant mutational hotspot (cancerhotspots.org negative) and not clearly within the structurally defined tyrosine kinase domain (aa ~510–781). Domain-level PM1 cannot be applied without stronger evidence. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant
- exact variant not listed.
- Residue 492 is in the juxtamembrane region
- adjacent to SHC-binding Y490
- but not within the kinase domain.
Still missing
- Structural/domain annotation confirming critical functional domain spanning residue 492 would allow PM1 application.
Sources
PM5 No pathogenic missense variant at the same residue (p.Glu492) with a different amino acid substitution was identified. The PM5 candidate harvesting pipeline returned no eligible comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue pathogenic comparators.
PM6 No de novo observation with confirmed maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- No confirmed de novo events in ClinVar or reviewed literature.
PP5 ClinVar classification for this variant is Uncertain Significance (Variation ID 418887, review status: criteria provided, single submitter). There are no expert panel (3-star) submissions. The majority of clinical laboratories (7/8) classify as Uncertain Significance; one classifies as Likely benign. PP5 requires a reputable source reporting the variant as pathogenic, which is not met here. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 418887: Uncertain Significance (7 submissions)
- Likely benign (1 submission).
- No expert panel review (0 three-star submissions).
- Review status: criteria provided
- single submitter.
Sources
BA1 Allele frequency in gnomAD v4.1 is 0.069% (1,113/1,613,264 alleles), well below the 1% BA1 threshold. Not applicable. Details ▾Hide ▴
BS1 Allele frequency in gnomAD v4.1 is 0.069%, below the 0.3% BS1 threshold. Not applicable. Details ▾Hide ▴
BS3 Functional studies from PMID:33235206 demonstrate that NTRK1 E492K impairs TrkA function: reduced neurite outgrowth in patient-derived neural stem cells, reduced NTRK1 expression, and altered signaling in a knock-in mouse model. These findings do not support a benign functional effect; they support a deleterious impact. Details ▾Hide ▴
Evidence considered
- E492K NSCs showed reduced neurite growth and reduced NTRK1 expression (damaging
- not benign).
Sources
BS4 No evidence of non-segregation with disease was identified. The variant co-segregates with disease in the one family studied (PMID:33235206). Details ▾Hide ▴
Evidence considered
- No non-segregation data available
- observed co-segregation in one family.
BP1 NTRK1-associated CIPA/HSAN4 is caused by both missense and truncating variants. Multiple missense NTRK1 variants have been reported as pathogenic in CIPA, including the variant under assessment. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NTRK1 CIPA is caused by both missense (e.g.
- p.Cys133Trp
- p.Glu492Lys) and nonsense/frameshift variants.
- BP1 is for genes where only truncating variants cause disease.
Sources
BP2 No evidence that this variant has been observed in trans with a known pathogenic NTRK1 variant in a healthy individual. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic variant reported.
BP4 Multiple computational tools predict a damaging effect: REVEL score 0.757 (>0.5 damaging threshold), PolyPhen-2 score 0.99 (probably damaging). BayesDel 0.297 is discordant but does not outweigh the REVEL prediction. BP4 requires multiple lines of computational evidence suggesting no impact, which is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL 0.757 predicts damaging
- does not support BP4.
- PolyPhen-2 0.99 predicts damaging.
- BayesDel 0.297 is discordant.
Sources
BP5 No evidence was identified that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No case with alternate molecular etiology identified.
BP6 Only 1 of 8 ClinVar submissions classifies this variant as Likely benign (Labcorp/Invitae, SCV000752362). The remaining 7 classify as Uncertain Significance. No expert panel (3-star) review exists. BP6 requires a reputable source reporting the variant as benign; a single Likely benign submission without expert panel consensus does not satisfy this criterion. Details ▾Hide ▴
Evidence considered
- ClinVar: 7 Uncertain Significance
- 1 Likely benign.
- No expert panel review.
- Single Likely benign classification does not constitute reputable source consensus.
Sources
PS5 No alternative nucleotide substitution at the same codon producing p.Glu492Lys with an established pathogenic classification was identified. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 492 producing p.Glu492Lys found in ClinVar or literature.
Not assessed · 1 · no assessment recorded
PP2 Insufficient gene-level constraint data (e.g., missense Z-score, gnomAD constraint metrics) for NTRK1 to determine whether the gene has a low rate of benign missense variation. PP2 cannot be applied without this metric. Details ▾Hide ▴
Evidence considered
- No NTRK1 missense constraint metric available in the evidence brief.
Still missing
- gnomAD missense constraint Z-score or o/e metric for NTRK1 needed.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002529.3:c.1474G>A (p.Glu492Lys) is a missense substitution; it does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- does not meet PVS1 null-variant criteria.
Sources
BP7 N/ANM_002529.3:c.1474G>A is a missense variant (p.Glu492Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants.
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.1474G>A
- Protein (HGVS p.)
- NP_002520.2:p.(Glu492Lys)
- GRCh38
- chr1:156875639 G>A
- GRCh37
- chr1:156845431 G>A
- ClinVar
- 418887
- COSMIC
- COSV62324977
Gene diagram
Every interpreted variant in NTRK1, mapped onto the exon structure of NM_002529.3. Select a row to find it on the plot.
NTRK1NM_002529.3
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 NTRK1
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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
1,113 / 1,613,264 alleles
AF 0.00069 · 1 homozygotes · FAF 0.000845
gnomAD v2.1
124 / 282,262 alleles
AF 0.000439 · 0 homozygotes · FAF 0.000708
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00069 · 1113 / 1,613,264 alleles · 1 hom · FAF 0.00085
| European (non-Finnish)1051 / 1,179,968 | 0.000891 hom |
| Remaining individuals32 / 62,476 | 0.00051 |
| African/African American12 / 74,796 | 0.00016 |
| European (Finnish)9 / 63,584 | 0.00014 |
| Admixed American8 / 59,962 | 0.00013 |
| East Asian1 / 44,838 | 2.2e-05 |
0 alternate alleles recorded in 4 other groups: Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00044 · 124 / 282,262 alleles · 0 hom · FAF 0.00071
| European (non-Finnish)105 / 128,976 | 0.00081 |
| Remaining individuals3 / 7,218 | 0.00042 |
| African/African American7 / 24,936 | 0.00028 |
| Admixed American5 / 35,422 | 0.00014 |
| European (Finnish)3 / 24,778 | 0.00012 |
| East Asian1 / 19,948 | 5e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000689906; MAF= 0.06899%, 1113/1613264 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000890702; MAF= 0.08907%, 1051/1179968 alleles, homozygotes = 1); grpmax FAF= 0.00084528.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000439308; MAF= 0.04393%, 124/282262 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000814105; MAF= 0.08141%, 105/128976 alleles, homozygotes = 0); grpmax FAF= 0.00070845.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.757
- BayesDel
- 0.297
How the predictions were used
PP3 SupportingIn silico prediction tools support a deleterious effect: REVEL score 0.757 (damaging threshold >0.5); PolyPhen-2 score 0.99 (probably damaging) reported in PMID:33235206. BayesDel score 0.297 is discordant but REVEL is the verified predictor in this pipeline. SpliceAI max delta 0.08 indicates no splicing impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.757 (damaging).
- PolyPhen-2: 0.99 (probably damaging).
- BayesDel: 0.297 (discordant
- below damaging threshold).
- SpliceAI max delta: 0.08 (no splicing impact).
Sources
BP4 Multiple computational tools predict a damaging effect: REVEL score 0.757 (>0.5 damaging threshold), PolyPhen-2 score 0.99 (probably damaging). BayesDel 0.297 is discordant but does not outweigh the REVEL prediction. BP4 requires multiple lines of computational evidence suggesting no impact, which is not satisfied. Details ▾Hide ▴
Evidence considered
- REVEL 0.757 predicts damaging
- does not support BP4.
- PolyPhen-2 0.99 predicts damaging.
- BayesDel 0.297 is discordant.
Sources
BP7 N/ANM_002529.3:c.1474G>A is a missense variant (p.Glu492Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.757. BayesDel score = 0.296765.
9 paper records listed. 2 cited in the classification.
Cited in the classification
-
PMID 24154508 ↗Progress in peripheral nerve disease research in the last two years.Evans M et al. · 2013 DecReview of Davidson et al. (PMID:22302274) describing the UK HSAN cohort. A novel homozygous NTRK1 missense mutation p.Glu492Lys was identified in a patient with a congenital syndrome consisting of sensory neuropathy, anhidrosis, seizures, deafness, and developmental delay — a phenotype consistent with CIPA/HSAN4.→ PP4 Names this variant
Source detail
A novel homozygous missense mutation (p.Glu492Lys) resulting in a congenital syndrome consisting of sensory neuropathy, anhidrosis, seizures, deafness and developmental delay was also found.
Location Genetic advances section, paragraph 3 (describing Davidson et al. findings)
Context Not applicable (review article; cites primary data from Davidson et al. 2012)
-
PMID 33235206 ↗Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice.Nakajima K et al. · 2020 Nov 24NTRK1 E492K (c.1474G>A, p.Glu492Lys) identified in a large multiplex family where it co-segregates with ADTKD and mood disorders including bipolar disorder. Patient-derived iPSC neural stem cells carrying E492K showed reduced neurite outgrowth upon NGF treatment and markedly reduced NTRK1 gene expression. A conditional knock-in mouse model (E495K, mouse ortholog) exhibited altered hippocampal pERK signaling. The authors note that homozygous E492K can cause CIPA.→ PS3 → PP1 Names this variant
Source detail
we identified a E492K mutation in the NTRK1 gene that is approximately 1 Mb distal to MUC1
Location Abstract; Results (NTRK1 mutation identification, Functional analysis sections); Discussion
Context iPSC-derived neural stem cells from proband and unaffected relative; neurite outgrowth assay with NGF treatment; qPCR for NTRK1 expression; conditional E495K knock-in mouse model (hippocampal pERK analysis)
Other recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015The ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a methodological guideline paper that does not mention any specific variant, including NM_002529.3:c.1474G>A (p.Glu492Lys).Does not name this variant
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PMID 27058611 ↗De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.Priest JR et al. · 2016Study of de novo and rare variants in atrioventricular septal heart defects. NTRK1 was not mentioned in the full text; NM_002529.3:c.1474G>A was not identified in this paper.Does not name this variant
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PMID 27698470 ↗Exome sequencing in the knockin mice generated using the CRISPR/Cas system.Nakajima K et al. · 2016Technical methods paper describing exome sequencing quality control in CRISPR/Cas9-generated knock-in mice. NTRK1 was not mentioned in the full text; NM_002529.3:c.1474G>A was not identified.Does not name this variant
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PMID 32707200 ↗Whole-Exome Sequencing of Patients With Posterior Segment Uveitis.Li AS et al. · 2021Whole-exome sequencing study of patients with posterior segment uveitis. NTRK1 was not mentioned in the full text; NM_002529.3:c.1474G>A was not identified in this paper.Does not name this variant
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PMID 20301532 ↗Charcot-Marie-Tooth Hereditary Neuropathy Overview.Adam MP et al. · 1993GeneReviews overview of Charcot-Marie-Tooth hereditary neuropathy. This is a general review of CMT genetics; full text was not available in the case folder, but the abstract and topic do not pertain to NTRK1 or the c.1474G>A variant.Does not name this variant
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PMID 20301726 ↗NTRK1 Congenital Insensitivity to Pain with Anhidrosis.Adam MP et al. · 1993GeneReviews overview of NTRK1-related congenital insensitivity to pain with anhidrosis. This is a general clinical summary of CIPA; full text was not available in the case folder, and there is no indication that the specific c.1474G>A variant is discussed.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological paper describing the Sherloc classification framework. It does not discuss specific NTRK1 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,113 / 1,613,264 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.080
Open source ↗
ClinVar
6 Uncertain significance · 1 Uncertain Significance · 1 Likely benign
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/418887/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156845431-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156875639-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156875639-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.1474…
- OncoKB ↗www.oncokb.org/gene/NTRK1/E492K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=184493607
- 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= 0.000689906; MAF= 0.06899%, 1113/1613264 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000890702; MAF= 0.08907%, 1051/1179968 alleles, homozygotes = 1); grpmax FAF= 0.00084528.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000439308; MAF= 0.04393%, 124/282262 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000814105; MAF= 0.08141%, 105/128976 alleles, homozygotes = 0); grpmax FAF= 0.00070845.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 418887)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.757. BayesDel score = 0.296765.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62324977, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.