Variant classification summary

NM_002529.3:c.1474G>A

NTRK1 · NP_002520.2:p.(Glu492Lys) · NM_002529.3

GRCh37: chr1:156845431 G>A · GRCh38: chr1:156875639 G>A

Gene: NTRK1 Transcript: NM_002529.3

Final call

Likely Pathogenic

PS3 moderate PM2 supporting PP1 supporting PP3 supporting PP4 supporting BS2 supporting benign

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Glu492Lys)

gnomAD AF

0.0006899056818970733 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

6

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.

7

ClinVar classification is Uncertain Significance (Variation ID 418887, 7 submissions) with one Likely benign submission; no expert panel review exists.

8

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	No de novo occurrence with confirmed maternity and paternity was identified for this variant.
PS3	Met	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.	PMID:33235206
PS4	Not met	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.
PS5	Not met	No alternative nucleotide substitution at the same codon producing p.Glu492Lys with an established pathogenic classification was identified.
PM1	Not met	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.	PMID:33235206
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.
PM6	Not met	No de novo observation with confirmed maternity and paternity was identified for this variant.
PP1	Met	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.	PMID:33235206
PP2	Not assessed	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.
PP3	Met	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.	revel bayesdel spliceai PMID:33235206
PP4	Met	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.	PMID:24154508
PP5	Not met	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.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 0.069% (1,113/1,613,264 alleles), well below the 1% BA1 threshold. Not applicable.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 0.069%, below the 0.3% BS1 threshold. Not applicable.	gnomad_v4
BS2	Met	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.	gnomad_v4
BS3	Not met	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.	PMID:33235206
BS4	Not met	No evidence of non-segregation with disease was identified. The variant co-segregates with disease in the one family studied (PMID:33235206).
BP1	Not met	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.	PMID:24154508
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic NTRK1 variant in a healthy individual.
BP4	Not met	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.	revel bayesdel PMID:33235206
BP5	Not met	No evidence was identified that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	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.	clinvar
BP7	N/A	NM_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.

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