Variant classification summary

NM_006182.3:c.298G>A

DDR2 · NP_006173.2:p.(Val100Met) · NM_006182.3

GRCh37: chr1:162724526 G>A · GRCh38: chr1:162754736 G>A

Gene: DDR2 Transcript: NM_006182.3

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

DDR2

Transcript

NM_006182.3

Protein

NP_006173.2:p.(Val100Met)

gnomAD AF

1.2390759962480778e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006182.3:c.298G>A (p.Val100Met) is a missense variant in DDR2, a receptor tyrosine kinase gene in which missense variants cause spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL).

2

This variant is extremely rare in population databases: absent from gnomAD v2.1 and present at 2/1,614,106 alleles (AF=1.24e−06) in gnomAD v4.1, with a grpmax filtering allele frequency of 2.8e−07, meeting PM2 at moderate strength.

3

In silico prediction tools support a deleterious effect: REVEL score 0.883 (strongly pathogenic), meeting PP3 at supporting strength.

4

The variant is absent from ClinVar with no classifications from any submitter. No variant-specific functional data, de novo observations, or segregation information were available for assessment.

5

Available evidence includes one moderate pathogenic criterion (PM2) and one supporting pathogenic criterion (PP3). No benign criteria are met. This evidence is insufficient to classify the variant as pathogenic or likely pathogenic under the ACMG/AMP 2015 framework. The variant is classified as a Variant of Uncertain Significance (VUS).

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_006182.3:c.298G>A (p.Val100Met) is a missense variant and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic variant with the same amino acid change (p.Val100Met) arising from a different nucleotide substitution has been identified in ClinVar or the literature. This variant is absent from ClinVar entirely.	clinvar
PS2	Not assessed	No proband phenotype, family history, or parental genotype data were provided. De novo status cannot be evaluated without trio sequencing or confirmed parental relationships.
PS3	Not met	No variant-specific functional studies or systematic range characterization that includes codon 100 were identified in the literature. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. COSMIC reports no entries for this variant in somatic cancers.	oncokb
PS4	Not assessed	No case/control data or affected-vs-unaffected prevalence statistics were provided. The variant is absent from ClinVar, precluding any submitter-based case counting.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. The established criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5, BA1, BS1-BS4, and BP1-BP7. No CSPEC/VCEP framework applies a PS5 criterion for DDR2.	generic_acmg_combination_rules
PM1	Not met	The variant p.Val100Met lies within the discoidin domain of DDR2, but it does not fall within a statistically significant mutational hotspot (cancerhotspots.org). No evidence was identified that codon 100 resides within a well-characterized functional domain lacking benign variation, which would be required to satisfy PM1 absent a hotspot designation.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (total AF=1.24e−06; 2/1,614,106 alleles; 0 homozygotes; grpmax FAF=2.8e−07), well below the 0.1% threshold for PM2 application. The highest subpopulation frequency is in European (non-Finnish) at 1.69e−06 (2/1,179,998 alleles).	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants (different missense change at codon 100) classified as pathogenic or likely pathogenic were identified in ClinVar. The automated PM5 candidate search returned zero candidates.	pm5_candidates clinvar
PM6	Not assessed	No de novo data or parental genotype information was available. PM6 requires confirmation that the variant arose de novo in a proband, which cannot be assessed without trio sequencing data.
PP1	Not assessed	No family segregation data, pedigree, or co-segregation analysis was provided. PP1 cannot be evaluated without information on variant transmission in affected relatives.
PP2	Not assessed	DDR2 missense variants are an established disease mechanism for SMED-SL (per PMID:24725993), but PP2 additionally requires evidence of a low rate of benign missense variation in the gene (high missense constraint). The HCI prior is not available for DDR2, and gnomAD missense constraint metrics (Z-score) were not provided in the evidence brief.	pvs1_gene_context
PP3	Met	Multiple in silico prediction tools support a deleterious effect. REVEL score is 0.883 (strongly pathogenic; well above the 0.75 threshold). BayesDel score is 0.566 (intermediate, leaning deleterious). SpliceAI predicts no splicing impact (max delta=0.01), consistent with a missense-only effect. The high REVEL score provides supporting evidence for pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical information was provided. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene (SMED-SL for DDR2), which cannot be evaluated without clinical data.
PP5	Not met	This variant is absent from ClinVar. No reputable source (3-star expert panel or equivalent) has classified this variant as pathogenic or likely pathogenic. There is no ClinVar submission to evaluate.	clinvar
BA1	Not met	The variant frequency in gnomAD v4.1 (AF=1.24e−06, 0.00012%) is orders of magnitude below the BA1 threshold of 1% (>0.01). This variant is extremely rare in the general population.	gnomad_v4
BS1	Not met	The variant frequency in gnomAD v4.1 (AF=1.24e−06, 0.00012%) is well below the BS1 threshold of >0.3%. It is too rare to support a benign interpretation based on population frequency.	gnomad_v4
BS2	Not assessed	No information was provided about whether this variant has been observed in healthy adults at an age when full penetrance of DDR2-related disease (SMED-SL) would be expected. Without clinical phenotype data for the 2 gnomAD carriers, BS2 cannot be applied.
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect for this variant were identified. OncoKB reports no reviewed functional evidence, and the literature pass returned zero PMIDs with variant-specific functional data.	oncokb
BS4	Not assessed	No family segregation data were provided. BS4 requires non-segregation of the variant with disease in affected family members, which cannot be evaluated without pedigree information.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants are a known disease mechanism. DDR2 missense variants are an established cause of SMED-SL (PMID:24725993: 'SMED-SL is reported to be caused by missense or splice site mutations in DDR2'), so BP1 does not apply.	pvs1_gene_context
BP2	Not assessed	No phase data or co-occurrence information with a known pathogenic variant in DDR2 was available. BP2 cannot be evaluated without trans-phase confirmation.
BP4	Not met	Multiple in silico predictors support a deleterious rather than benign effect. REVEL score is 0.883 (strongly pathogenic). BayesDel is 0.566 (intermediate, not clearly benign). SpliceAI delta is 0.01 (no splice impact, but this does not indicate a benign effect). The computational evidence does not support a benign interpretation.	revel bayesdel spliceai
BP5	N/A	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No alternate molecular diagnosis was identified or provided for this case.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified it as benign or likely benign. There are no expert panel benign classifications to reference.	clinvar
BP7	N/A	NM_006182.3:c.298G>A is a missense variant (p.Val100Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI delta of 0.01 confirms no cryptic splice effect, but the criterion is categorically inapplicable to missense substitutions.	spliceai
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_006182.3:c.298G>A is a substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. No evidence of biallelic DDR2 variants or trans-phase data was available.
PM4	N/A	PM4 applies to protein-length changing variants (in-frame deletions/insertions, stop-loss). NM_006182.3:c.298G>A is a missense substitution and does not alter protein length.

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