Variant classification summary

NM_002529.3:c.926C>T

NTRK1 · NP_002520.2:p.(Pro309Leu) · NM_002529.3

GRCh37: chr1:156843500 C>T · GRCh38: chr1:156873708 C>T

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 supporting

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Pro309Leu)

gnomAD AF

0.0 (v2.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002529.3:c.926C>T (p.Pro309Leu) in NTRK1 is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.

2

One supporting pathogenic criterion was met: PM2 (absent from gnomAD v2.1 and v4.1 population databases).

3

No benign criteria were met. Population absence does not support BA1 (>1%), BS1 (>0.3%), or BS2 (no homozygotes observed). In silico predictions are mixed (REVEL 0.554 damaging; BayesDel 0.172 neutral; SpliceAI 0.00 no splice effect), preventing application of either PP3 or BP4.

4

Only one supporting-level criterion (PM2) was met, which is insufficient to reach Likely Pathogenic or Likely Benign under the ACMG/AMP 2015 combination rules. The variant remains as Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 is not applicable to missense variants. NM_002529.3:c.926C>T is a missense change (p.Pro309Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required by the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	PS1 requires the same amino acid change (Pro309Leu) to have been previously established as pathogenic. The ClinVar record for this exact variant (VariationID 526728) is classified as Uncertain Significance by a single submitter, not Pathogenic. No independent evidence establishes Pro309Leu as a pathogenic change.	clinvar
PS2	N/A	No de novo evidence is available. No parental sequencing data or de novo reports exist in the case materials for NM_002529.3:c.926C>T.
PS3	Not met	No functional studies have been performed on NM_002529.3:c.926C>T (p.Pro309Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. The single COSMIC entry (COSV62323938, n=1) reflects somatic observation, not experimental functional characterization. No publications with experimental functional data for this variant were identified in the literature pass or among the reviewed papers.	oncokb
PS4	Not met	No case-level evidence was identified for this variant. The PS4 screen returned zero qualifying cases. PMIDs 20301726 and 29419974 are GeneReviews overview chapters on NTRK1-related congenital insensitivity to pain — they do not report this specific variant. The single ClinVar submission (SCV000752360, Labcorp/Invitae) does not provide case counts or affected individual data.	clinvar PMID:20301726 PMID:29419974
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 variant interpretation framework. There is no applicable evidence pathway for this criterion under the generic ACMG fallback rules.	generic_acmg_combination_rules
PM1	Not met	PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation. Cancerhotspots.org does not identify residue 309 as a statistically significant hotspot. While NTRK1 position 309 lies in the extracellular leucine-rich repeat domain involved in ligand binding, no domain-level mutational constraint data or CSPEC/VCEP domain specification was available to support PM1 application under generic ACMG rules.
PM2	Met	NM_002529.3:c.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1 (0 alleles). Under generic ACMG/AMP rules, absence from population databases at an allele frequency below 0.1% supports PM2 at supporting strength for a missense variant without additional corroborating evidence.	gnomad_v2 gnomad_v4
PM5	Not met	PM5 requires a different pathogenic missense change at the same amino acid residue (Pro309). No same-residue comparator variants classified as pathogenic or likely pathogenic were identified in ClinVar. The automated PM5 candidate harvest returned zero candidates.
PM6	N/A	No de novo observations exist for NM_002529.3:c.926C>T. PM6 requires an assumed or confirmed de novo event with no confirmation of paternity and maternity, which is unavailable for this variant.
PP1	N/A	No segregation data is available. PP1 requires co-segregation of the variant with disease in multiple affected family members, which has not been assessed for NM_002529.3:c.926C>T.
PP2	Not met	PP2 requires a low rate of benign missense variation in the gene with missense variants being a common disease mechanism. While NTRK1 loss-of-function is an established mechanism for congenital insensitivity to pain with anhidrosis (CIPA) and missense variants are observed in CIPA, formal constraint metrics (e.g., gnomAD missense Z-score, HCI prior) were not available for NTRK1 to support application of PP2 under generic ACMG rules.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.554 (borderline damaging, just above the 0.5 threshold). BayesDel score is 0.172 (neutral-to-benign range). SpliceAI predicts no splice impact (max delta = 0.00). With only one in silico tool suggesting a potentially damaging effect and others indicating neutrality, the evidence does not meet the threshold for multiple lines supporting a deleterious prediction.	revel bayesdel spliceai
PP4	N/A	No patient phenotype information was provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic, with the evidence not available for independent review. The ClinVar classification for NM_002529.3:c.926C>T is Uncertain Significance (VariationID 526728, 1 clinical laboratory, review status: criteria provided, single submitter). This is not a pathogenic assertion and does not meet the 3-star expert panel threshold. The ClinVar-linked PMIDs (20301726, 29419974) are GeneReviews overviews that do not classify this specific variant as pathogenic.	clinvar PMID:20301726 PMID:29419974
BA1	Not met	BA1 requires allele frequency >1% in population databases. NM_002529.3:c.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency >0.3% in population databases. NM_002529.3:c.926C>T is absent from gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult in a homozygous or hemizygous state (or in trans with a pathogenic variant for dominant disorders). NM_002529.3:c.926C>T has zero homozygotes in gnomAD and no observations in trans with a pathogenic variant have been reported.	gnomad_v2
BS3	Not met	BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on NM_002529.3:c.926C>T (p.Pro309Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
BS4	N/A	No segregation data is available. BS4 requires lack of segregation with disease in affected family members.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which only truncating variants are known to cause disease. NTRK1-related congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants, so BP1 does not apply.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder. No phase information is available for NM_002529.3:c.926C>T.
BP4	Not met	BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product. REVEL score is 0.554 (damaging prediction, above 0.5 threshold), which contradicts a no-impact prediction. BayesDel score is 0.172 (neutral-tending but not strongly benign), and SpliceAI predicts no splice effect (max delta = 0.00). The REVEL result alone prevents BP4 from being met, as there is not consensus among computational tools suggesting a benign effect.	revel bayesdel spliceai
BP5	N/A	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data is available in the case materials.
BP6	Not met	BP6 requires a reputable source to report the variant as benign with evidence not available for independent review. The ClinVar classification for NM_002529.3:c.926C>T is Uncertain Significance (VariationID 526728, 1 submitter), not benign. No expert panel has classified this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.926C>T is a missense variant (p.Pro309Leu), not synonymous.

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