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.1 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).2 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.3 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.4
DDR2
Final classification
VUS
DDR2 c.1723G>C · p.Gly575Arg
DDR2
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.
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 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
DDR2 c.1723G>C
PM2 + PP3
→
VUS
Gene diagram
· NM_006182.3 · variants mapped to exon structure
DDR2
NM_006182.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF=1.42e-5 (4/282340)homozygotes=0
✓
PP3
supporting
Pathogenic
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: 0.972 (strongly pathogenic prediction).BayesDel: 0.558 (borderline pathogenic prediction).SpliceAI: max delta = 0.00 (no predicted splicing impact).
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant causing the same amino acid change (p.Gly575Arg) at this position has been identified in ClinVar or the literature.
PS2
No de novo data are available for NM_006182.3:c.1723G>C.
PS3
No variant-specific functional studies demonstrating a damaging effect have been identified.
PS4
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics).
PM1
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.
PM6
No de novo observation has been reported for NM_006182.3:c.1723G>C.
PP1
No segregation data are available for this variant.
PP2
DDR2 is associated with spondylo-meta-epiphyseal dysplasia (SMED-SL) via both missense and truncating variants.
PP4
No specific patient phenotype information is available for the individual(s) carrying this variant.
PP5
This variant is classified as Uncertain significance by a single clinical laboratory (Labcorp Genetics) in ClinVar.
Benign
BA1
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.
BS1
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.
BS2
No homozygous observations have been reported in gnomAD.
BS3
No functional studies demonstrating a benign effect have been identified for NM_006182.3:c.1723G>C.
BS4
No segregation data demonstrating lack of cosegregation with disease are available.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease.
BP2
No observation of this variant in trans with a known pathogenic DDR2 variant has been reported.
BP4
Multiple in silico tools predict a deleterious effect.
BP5
No case has been reported in which an alternative molecular basis for disease was identified in an individual carrying this variant.
BP6
No reputable source classifies this variant as benign or likely benign.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.57619e-06; MAF= 0.00056%, 9/1614004 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.0005e-05; MAF= 0.00500%, 3/59994 alleles, homozygotes = 0); grpmax FAF= 1.327e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.41673e-05; MAF= 0.00142%, 4/282340 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.65195e-05; MAF= 0.00565%, 2/35386 alleles, homozygotes = 0); grpmax FAF= 9.59e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,614,004
0 hom · FAF 0.0013%
0 hom · FAF 0.0013%
Admixed American 3 / 59,994 |
0.005% |
Remaining individuals 1 / 62,484 |
0.0016% |
European (non-Finnish) 5 / 1,180,018 |
0.00042% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0014%
· 4 / 282,340
0 hom · FAF 0.00096%
0 hom · FAF 0.00096%
Admixed American 2 / 35,386 |
0.0057% |
European (non-Finnish) 2 / 128,832 |
0.0016% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4701000)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.972. BayesDel score = 0.558463.
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. DDR2, a receptor tyrosine kinase, is mutated at low frequencies in various cancers.
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