NM_006182.3:c.1753A>G

DDR2 · NP_006173.2:p.(Met585Val) · NM_006182.3

GRCh37: chr1:162743283 A>G · GRCh38: chr1:162773493 A>G

Gene: DDR2 Transcript: NM_006182.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

DDR2

Transcript

NM_006182.3

Protein

NP_006173.2:p.(Met585Val)

gnomAD AF

2.7264131185085034e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

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.

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics). No expert panel has reviewed this variant.

No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified in the literature or databases.

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.

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	Missense variant (c.1753A>G, p.Met585Val); not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework per ClinGen SVI recommendations (PMC6185798) requires a null-variant bucket for default applicability. This variant falls into the 'other' bucket and does not qualify for PVS1.	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at codon 585 producing the same amino acid substitution (Met585Val) that has been characterized as pathogenic. PS1 requires a different variant at the same residue with the same amino acid change that is established pathogenic.
PS2	Not assessed	No de novo data available for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not assessed	No variant-specific functional studies identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and has no reviewed functional evidence. No publications reporting functional characterization of p.Met585Val were found.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. The variant is extremely rare in gnomAD but no disease-specific prevalence data exist. ClinVar contains only a single uncertain significance submission.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 requires a different nucleotide change at the same codon causing a different pathogenic missense change. No such comparator has been identified for codon 585 of DDR2.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot or a well-established critical functional domain without benign variation. Hotspot assessment confirms the residue is not in a significant hotspot.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variant at codon 585 of DDR2 that is pathogenic was identified in ClinVar. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not assessed	No de novo data available. PM6 requires confirmed de novo occurrence without confirmed maternity/paternity.
PP1	Not assessed	No segregation data available. PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2	Not assessed	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. While DDR2 missense variants are associated with SMED-SL, gene-level missense constraint metrics (e.g., Z-score, missense pLI) are not available in this case.
PP3	Not met	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). No computational evidence supports pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No detailed phenotype or clinical data available for individuals carrying this variant. PP4 requires the variant to be observed in a patient with a phenotype that is highly specific for DDR2-related disease.
PP5	Not met	This variant is reported in ClinVar as Uncertain Significance by a single clinical laboratory (Ambry Genetics). PP5 requires classification as pathogenic by a reputable source; a single VUS submission does not meet this threshold.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals observed in gnomAD v2.1 or v4.1. No evidence of observation in healthy adults lacking the DDR2-related phenotype. BS2 requires homozygous observation or observation in unaffected adults in a fully penetrant disorder.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies demonstrating a lack of damaging effect have been identified for this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.	oncokb
BS4	Not assessed	No segregation data available to demonstrate lack of co-segregation with disease. BS4 requires observation of non-segregation with disease in affected families.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. In DDR2, both missense and truncating variants are established causes of SMED-SL; missense variants are a known disease mechanism, so BP1 does not apply.	pvs1_gene_context
BP2	Not assessed	No data on observation in trans with a known pathogenic DDR2 variant. BP2 requires observation in trans (or in cis with or without) a pathogenic variant in a recessive disorder.
BP3	N/A	Variant type is a substitution; BP3 applies to in-frame deletions/insertions in repetitive regions — not applicable to single-nucleotide substitutions.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No case identified with an alternate molecular basis for disease. BP5 requires observation in a case where an alternate cause is found.
BP6	Not assessed	No reputable source reports this variant as benign. BP6 requires a reputable source reporting the variant as benign. ClinVar classifies it as VUS, not benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.1753A>G, p.Met585Val), not synonymous, so BP7 is not applicable regardless of SpliceAI predictions.
PM3	N/A	Insufficient data to assess recessive inheritance. PM3 requires observation in trans with a pathogenic variant. No phase data available.
PM4	N/A	Variant type is a substitution; PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss) — not applicable to single-nucleotide missense substitutions.

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