NM_002253.3:c.2300T>C

KDR · NP_002244.1:p.(Ile767Thr) · NM_002253.3

GRCh37: chr4:55964937 A>G · GRCh38: chr4:55098770 A>G

Gene: KDR Transcript: NM_002253.3

Final call

VUS

PM2 moderate

Variant details

Gene

KDR

Transcript

NM_002253.3

Protein

NP_002244.1:p.(Ile767Thr)

gnomAD AF

1.8596439897546013e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002253.3:c.2300T>C (p.Ile767Thr) is a missense variant in the KDR gene, located in the transmembrane domain.

This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1 (allele frequency 1.86e-06, 3/1,613,212 alleles), meeting PM2 at moderate strength.

The variant is absent from gnomAD-Canada v1.0 and not reported in COSMIC.

In silico predictions are equivocal: SpliceAI predicts no splice impact (max delta 0.00), REVEL score is 0.575 (borderline), and BayesDel is -0.004 (neutral). Neither PP3 nor BP4 is met.

The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics). No submitter has classified it as pathogenic or benign.

OncoKB classifies KDR I767T as Unknown Oncogenic Effect with no curated functional evidence. No published functional studies or case-level data specific to this variant were identified.

No CSPEC or VCEP framework exists for KDR. Assessment follows generic ACMG/AMP 2015 guidelines.

The single met criterion is PM2 (moderate). No pathogenic criteria at supporting strength or higher are met beyond PM2. Insufficient evidence is available to reach a likely pathogenic or pathogenic classification.

Insufficient benign evidence is available to reach a likely benign or benign classification. The variant remains a variant of 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	NM_002253.3:c.2300T>C is a missense variant (p.Ile767Thr) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No evidence of a different pathogenic nucleotide change at the same amino acid position (p.Ile767) was identified in ClinVar or the literature. Without a known pathogenic comparator variant at this codon, PS1 cannot be applied.
PS2	Not assessed	No de novo occurrence data with confirmed paternity and maternity are available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for this variant. OncoKB classifies it as Unknown Oncogenic Effect with no reviewed functional evidence. No variant-specific functional data were found in the published literature.	oncokb
PS4	Not assessed	No case-control studies or prevalence comparisons in affected vs. unaffected individuals are available. The variant is reported as VUS by a single clinical laboratory (Ambry Genetics) with no supporting case-level data.	clinvar
PS5	Not assessed	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (single submitter).	clinvar
PM1	Not met	The variant p.Ile767Thr is located in the transmembrane domain of KDR (VEGFR2), not in a statistically significant mutational hotspot. Hotspot analysis returned no significant enrichment at this residue. There is no curated evidence that the transmembrane region constitutes a critical functional domain for PM1 application in the absence of supporting case-level data.	oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1 (allele frequency 1.86e-06, 3/1,613,212 alleles, 0.00019%), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. The grpmax filtering allele frequency is 2.8e-07.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	No pathogenic missense variant at the same amino acid residue (p.Ile767) was identified in ClinVar or published literature to serve as a PM5 comparator. Automated PM5 candidate harvesting found no eligible same-residue candidates.	pm5_candidates
PM6	Not assessed	No de novo occurrence data (with or without confirmed parentage) are available for this variant.
PP1	Not assessed	No cosegregation data in affected family members are available for this variant.
PP2	Not assessed	Insufficient data to determine whether KDR has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. The gene-disease association for KDR in the germline context is limited to research-level evidence (familial Hodgkin lymphoma predisposition) and lacks established gene-disease validity.	pvs1_gene_context
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta 0.00). REVEL score is 0.575 (borderline, below typical pathogenic thresholds). BayesDel score is -0.004 (neutral, slightly benign-leaning). The in silico evidence is equivocal and does not satisfy PP3.	spliceai revel bayesdel
PP4	Not assessed	No proband phenotype or family history information is available to assess whether the clinical presentation is highly specific for KDR-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter — Ambry Genetics).	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 1.86e-06 (0.00019%), far below the 1% BA1 threshold for non-VCEP frameworks.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 1.86e-06 (0.00019%), far below the 0.3% BS1 threshold for non-VCEP frameworks. This frequency is not greater than expected for the disorder.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult individuals are available to assess BS2.
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing are available for this variant.
BS4	Not assessed	No family-based cosegregation data are available to assess lack of segregation in affected family members.
BP1	Not met	While KDR has literature-level support for loss-of-function as a disease mechanism in germline predisposition (familial Hodgkin lymphoma), there is insufficient evidence that KDR-related disease is caused primarily by truncating variants as opposed to missense variants. The gene-disease association remains at a research level and does not meet the threshold for BP1 application.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic variant in KDR or in cis with a pathogenic variant are available.
BP4	Not met	Multiple lines of computational evidence do not consistently suggest no impact. SpliceAI shows no splice effect (max delta 0.00). However, REVEL score is 0.575, which is borderline pathogenic-leaning and does not support benign interpretation. BayesDel is -0.004 (neutral). The in silico evidence is mixed and does not meet the requirement for multiple lines of evidence suggesting no impact on gene product.	spliceai revel bayesdel
BP5	Not assessed	No data are available identifying an alternate molecular basis for disease in a proband carrying this variant.
BP6	Not met	No reputable source has reported this variant as benign. ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants. NM_002253.3:c.2300T>C is a missense variant (p.Ile767Thr), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders (detection in trans with a pathogenic variant). KDR-related germline conditions do not have established recessive inheritance; the available literature suggests dominant or uncertain inheritance patterns.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). This variant is a missense substitution and does not alter protein length.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.