DVL1

Chr 1AD

dishevelled segment polarity protein 1

Also known as: DRS2, DVL, DVL1L1

NCBI Gene: 1855 ENSG00000107404 UniProt: O14640

DVL1, the human homolog of the Drosophila dishevelled gene (dsh) encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification. DVL1 is a candidate gene for neuroblastomatous transformation. The Schwartz-Jampel syndrome and Charcot-Marie-Tooth disease type 2A have been mapped to the same region as DVL1. The phenotypes of these diseases may be consistent with defects which might be expected from aberrant expression of a DVL gene during development. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Robinow syndrome, autosomal dominant 2MIM #616331

Active trials

Pathogenic / LP

388

ClinVar variants

Pubs (1 yr)

-1.1

Missense Z

0.73

LOEUF

Clinical Summary— DVL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

25 Pathogenic / Likely Pathogenic· 204 VUS of 388 total submissions

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GeneReview available — DVL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.73LOEUF

pLI 0.000

Z-score 2.69

OE 0.47 (0.31–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

-1.13Z-score

OE missense 1.14 (1.07–1.23)

554 obs / 484.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.47 (0.31–0.73)

0≤0.351.4

Missense OE1.14 (1.07–1.23)

0≤0.61.4

Synonymous OE1.44

0≤1.21.6

LoF obs/exp: 14 / 29.9Missense obs/exp: 554 / 484.2Syn Z: -4.97

DNGOF

Badonyi & Marsh 2024 ↗

0.80top 25%

GOF

0.7126th %ile

LOF

0.4037th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFurthermore, in contrast with the type of genetic alteration reported to cause WNT5A and ROR2 disease-associated mutations, variants in DVL1 seem to result in dominant-negative or gain-of-function proteins.PMID:25817016

GOFFurthermore, in contrast with the type of genetic alteration reported to cause WNT5A and ROR2 disease-associated mutations, variants in DVL1 seem to result in dominant-negative or gain-of-function proteins.PMID:25817016

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.