Variant classification summary

NM_006182.3:c.1723G>C

DDR2 · NP_006173.2:p.(Gly575Arg) · NM_006182.3

GRCh37: chr1:162742032 G>C · GRCh38: chr1:162772242 G>C

Gene: DDR2 Transcript: NM_006182.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

DDR2

Transcript

NM_006182.3

Protein

NP_006173.2:p.(Gly575Arg)

gnomAD AF

5.576194358873956e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006182.3:c.1723G>C (p.Gly575Arg) is a missense variant in exon 13 of DDR2. It is extremely rare in population databases, with a global allele frequency of 1.42e-05 in gnomAD v2.1 (4/282,340 alleles) and 5.58e-06 in gnomAD v4.1 (9/1,614,004 alleles), meeting PM2 at supporting strength.

2

REVEL predicts a deleterious score of 0.972, meeting PP3 at supporting strength. BayesDel (0.558) is consistent with this prediction. SpliceAI predicts no splicing impact (max delta = 0.00).

3

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics, variation ID 4701000). No functional studies, segregation data, de novo observations, or case-control data are available for this variant.

4

PVS1 is not applicable as this is a missense variant; PM5 is not applicable as no pathogenic missense variant at the same residue has been identified; BP7 is not applicable as this is not a synonymous variant.

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.1723G>C is a missense variant (p.Gly575Arg) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No established pathogenic variant causing the same amino acid change (p.Gly575Arg) at this position has been identified in ClinVar or the literature. PS1 cannot be assessed without such evidence.
PS2	Not assessed	No de novo data are available for NM_006182.3:c.1723G>C. The variant has not been reported in any trio or parentage-confirmed study.
PS3	Not assessed	No variant-specific functional studies demonstrating a damaging effect have been identified. OncoKB reports 'Unknown Oncogenic Effect' with no supporting PMIDs. No literature was found that directly tests NM_006182.3:c.1723G>C in a functional assay.	oncokb
PS4	Not assessed	This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics). No case-control studies, cohort analyses, or enriched case observations are available to assess PS4.	clinvar
PS5	Not assessed	No alternative pathogenic variant at the same amino acid position (Gly575) has been identified. The PM5 candidate search returned zero same-residue comparator variants with pathogenic classification.
PM1	Not assessed	Position 575 is within the DDR2 protein kinase domain (residues ~563-849), but no well-established critical functional domain with absent benign variation has been defined at this specific residue. The hotspot analysis did not identify this position as a statistically significant mutational hotspot. Without domain-specific benign variation data, PM1 cannot be reliably applied.
PM2	Met	NM_006182.3:c.1723G>C is absent from population databases at appreciable frequency. In gnomAD v2.1 the global allele frequency is 1.42e-5 (0.00142%, 4/282,340 alleles) and in gnomAD v4.1 it is 5.58e-6 (0.00056%, 9/1,614,004 alleles). The highest subpopulation frequency is 5.65e-5 (0.00565%) in Admixed American (gnomAD v2.1). All frequencies are well below the 0.1% threshold, and no homozygotes have been observed.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no pathogenic missense variant at the same amino acid position (Gly575) was identified in ClinVar or the literature.
PM6	Not assessed	No de novo observation has been reported for NM_006182.3:c.1723G>C. PM6 requires confirmed de novo occurrence with parentage confirmation.
PP1	Not assessed	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not assessed	DDR2 is associated with spondylo-meta-epiphyseal dysplasia (SMED-SL) via both missense and truncating variants. Insufficient data are available to determine whether DDR2 has a low rate of benign missense variation such that PP2 can be applied.
PP3	Met	Multiple in silico tools support a deleterious effect. REVEL predicts a damaging score of 0.972 (well above the 0.75 threshold). BayesDel score of 0.558 is borderline but consistent with a deleterious prediction. SpliceAI predicts no splicing impact (max delta = 0.00), which does not contradict the missense deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No specific patient phenotype information is available for the individual(s) carrying this variant. PP4 requires that the variant carrier's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not assessed	This variant is classified as Uncertain significance by a single clinical laboratory (Labcorp Genetics) in ClinVar. No reputable source has classified it as pathogenic or likely pathogenic.	clinvar
BA1	Not met	The highest observed population allele frequency is 5.65e-5 (0.00565%) in the Admixed American subpopulation (gnomAD v2.1), which is far below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The highest observed population allele frequency is 5.65e-5 (0.00565%) in the Admixed American subpopulation (gnomAD v2.1), which is far below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations have been reported in gnomAD. BS2 requires observation in a healthy adult homozygous state, or in trans with a pathogenic variant for a fully penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies demonstrating a benign effect have been identified for NM_006182.3:c.1723G>C.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation with disease are available.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. DDR2-related spondylo-meta-epiphyseal dysplasia (SMED-SL) is caused by both missense and splice site mutations; missense variants are a recognized disease mechanism. Therefore BP1 is not applicable.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic DDR2 variant has been reported.
BP4	Not met	Multiple in silico tools predict a deleterious effect. REVEL score of 0.972 strongly supports pathogenicity and contradicts a benign interpretation. BP4 cannot be applied when computational evidence supports a damaging effect.	revel bayesdel
BP5	Not assessed	No case has been reported in which an alternative molecular basis for disease was identified in an individual carrying this variant.
BP6	Not assessed	No reputable source classifies this variant as benign or likely benign. The sole ClinVar submission (Labcorp Genetics) classifies it as Uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants. NM_006182.3:c.1723G>C is a missense variant (p.Gly575Arg); BP7 is not applicable.

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.