This variant is a missense substitution (c.1753A>G, p.Met585Val) in DDR2, a receptor tyrosine kinase associated with autosomal recessive spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL).1 The variant is extremely rare in large population databases: present in 5 of 282,840 alleles in gnomAD v2.1 (AF=0.00177%) and 44 of 1,613,842 alleles in gnomAD v4.1 (AF=0.00273%), with no homozygotes observed. It is absent from gnomAD-Canada.2 Multiple in silico predictors (REVEL 0.261, BayesDel -0.199, SpliceAI max delta 0.01) consistently suggest a benign impact on protein function and splicing.3 This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics). No expert panel has reviewed this variant.4 No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified in the literature or databases.5 All publications associated with this variant through ClinVar are general policy statements on newborn screening and carrier screening; none mention DDR2 or the specific variant NM_006182.3:c.1753A>G.6
DDR2
Final classification
VUS
DDR2 c.1753A>G · p.Met585Val
DDR2
This variant is a missense substitution (c.1753A>G, p.Met585Val) in DDR2, a receptor tyrosine kinase associated with autosomal recessive spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL).
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
DDR2 c.1753A>G
PM2 + BP4
→
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
This variant is absent from gnomAD-Canada and extremely rare in general population databases (gnomAD v2.1: 5/282,840 alleles, AF=0.00177%; gnomAD v4.1: 44/1,613,842 alleles, AF=0.00273%). Both frequencies are well below the 0.1% PM2 threshold. No homozygotes observed in any population.
gnomAD v2.1 AF=0.00177% (5/2828400 hom)
✓
BP4
supporting
Benign
Multiple in silico predictors consistently support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative value consistent with benign), and SpliceAI max delta 0.01 (no splicing alteration predicted). All three computational tools agree on lack of damaging impact.
REVEL=0.261BayesDel=-0.199SpliceAI max delta=0.01. All predictors agree: no damaging effect.
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 585 producing the same amino acid substitution (Met585Val) that has been characterized as pathogenic.
PS2
No de novo data available for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls.
PM1
This variant does not lie in a statistically significant mutational hotspot or a well-established critical functional domain without benign variation.
PM6
No de novo data available.
PP1
No segregation data available.
PP2
PP2 requires evidence that missense variants are a common mechanism of disease in DDR2 and that the gene has a low rate of benign missense variation.
PP3
Multiple in silico predictors support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative, consistent with benign), and SpliceAI max delta 0.01 (no predicted splicing impact).
PP4
No detailed phenotype or clinical data available for individuals carrying this variant.
PP5
This variant is reported in ClinVar as Uncertain Significance by a single clinical laboratory (Ambry Genetics).
Benign
BA1
The maximum population allele frequency for this variant is 0.00400% (gnomAD v2.1 African/African American subpopulation), far below the 1% BA1 threshold for benign standing.
BS1
The maximum population allele frequency is 0.00400% (gnomAD v2.1 African/African American subpopulation), far below the 0.3% BS1 threshold for a benign allele frequency.
BS2
No homozygous individuals observed in gnomAD v2.1 or v4.1.
BS3
No functional studies demonstrating a lack of damaging effect have been identified for this variant.
BS4
No segregation data available to demonstrate lack of co-segregation with disease.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease.
BP2
No data on observation in trans with a known pathogenic DDR2 variant.
BP5
No case identified with an alternate molecular basis for disease.
BP6
No reputable source reports this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.72641e-05; MAF= 0.00273%, 44/1613842 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.47489e-05; MAF= 0.00347%, 41/1179892 alleles, homozygotes = 0); grpmax FAF= 2.585e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.76778e-05; MAF= 0.00177%, 5/282840 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00481e-05; MAF= 0.00400%, 1/24970 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0027%
· 44 / 1,613,842
0 hom · FAF 0.0026%
0 hom · FAF 0.0026%
European (non-Finnish) 41 / 1,179,892 |
0.0035% |
Remaining individuals 2 / 62,456 |
0.0032% |
African/African American 1 / 74,918 |
0.0013% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0018%
· 5 / 282,840
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
African/African American 1 / 24,970 |
0.004% |
European (non-Finnish) 4 / 129,156 |
0.0031% |
+ 6 not observed (Admixed 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 = 3080827)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.261. BayesDel score = -0.199945.
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
Triaged references · 5 PMIDs not cited in assessment
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
31022120 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
CLINVAR