NM_002529.3:c.1065C>A (p.Asn355Lys) is a missense variant in NTRK1, a gene in which loss-of-function variants cause autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA).1 This variant is absent from large population databases (gnomAD v2.1 and v4.1), supporting PM2 at moderate strength.2 In silico predictors are inconclusive: REVEL score is 0.372 (intermediate, not reaching pathogenic thresholds) and BayesDel is -0.315 (benign-leaning). SpliceAI predicts no splicing impact (max delta = 0.00). PP3 and BP4 are not met.3 No functional studies, de novo reports, cosegregation data, or ClinVar submissions were identified for this variant. PVS1 does not apply as the variant is a missense substitution, not a null variant.4 Only PM2 (moderate) is met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate criterion is insufficient to reach Likely Pathogenic or Likely Benign. The variant is classified as a Variant of Uncertain Significance (VUS).5
NTRK1
Final classification
VUS
NTRK1 c.1065C>A · p.Asn355Lys
NTRK1
NM_002529.3:c.1065C>A (p.Asn355Lys) is a missense variant in NTRK1, a gene in which loss-of-function variants cause autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
NTRK1 c.1065C>A
PM2
→
VUS
Gene diagram
· NM_002529.3 · variants mapped to exon structure
NTRK1
NM_002529.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
NM_002529.3:c.1065C>A is absent from both gnomAD v2.1 and gnomAD v4.1, large population databases encompassing over 250,000 alleles combined. This supports moderate evidence under PM2 (absent from population controls).
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 355 producing the same p.Asn355Lys missense that has been previously classified as pathogenic.
PS2
No reports of a confirmed de novo occurrence (with maternity and paternity confirmed) of NM_002529.3:c.1065C>A were identified in the available evidence.
PS3
No well-established functional studies specifically evaluating the p.Asn355Lys variant were identified.
PS4
The variant is absent from ClinVar in the primary evidence pipeline, so no affected proband counts or case-control comparison data are available.
PM1
Residue Asn355 is located in the leucine-rich repeat C-terminal (LRRCT) domain of NTRK1, a functionally important extracellular region.
PM6
No report of a presumed de novo occurrence (without confirmation of maternity/paternity) was identified for NM_002529.3:c.1065C>A in the available evidence.
PP1
No cosegregation data for NM_002529.3:c.1065C>A with CIPA or other NTRK1-related disease in multiple affected family members was identified in the available evidence.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
Multiple in silico tools do not consistently predict a deleterious effect.
PP4
No patient phenotype information is available for this case.
PP5
The variant is absent from ClinVar, and no reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic.
Benign
BA1
NM_002529.3:c.1065C>A is absent from gnomAD v2.1 and v4.1.
BS1
NM_002529.3:c.1065C>A is absent from gnomAD v2.1 and v4.1.
BS2
No data on observation of NM_002529.3:c.1065C>A in healthy adult individuals with full penetrance expected at an early age.
BS3
No well-established functional studies demonstrating that p.Asn355Lys has no damaging effect on protein function were identified.
BS4
No families were identified in which NM_002529.3:c.1065C>A fails to segregate with disease (i.e., non-segregation data).
BP2
No data on observation of NM_002529.3:c.1065C>A in trans with a known pathogenic NTRK1 variant in an unaffected individual, or in cis with a pathogenic variant in a fully penetrant dominant disorder.
BP4
Multiple in silico tools do not consistently predict no impact.
BP5
No case was identified where NM_002529.3:c.1065C>A was found in an individual with an alternate molecular basis for disease that would suggest the variant is not causative.
BP6
The variant is absent from ClinVar.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.372. BayesDel score = -0.315045.
Functional
Unknown Oncogenic Effect
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
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links