DVL1

Chr 1AD

dishevelled segment polarity protein 1

Also known as: DRS2, DVL, DVL1L1

NCBI Gene: 1855 ENSG00000107404 UniProt: O14640 OMIM: 601365

DVL1 encodes a cytoplasmic phosphoprotein that participates in Wnt signaling pathways by binding to frizzled receptors and transducing signals to downstream effectors, and plays a role in neuromuscular junction formation through regulation of acetylcholine receptor clustering. Mutations cause autosomal dominant Robinow syndrome type 2, a skeletal dysplasia syndrome. The gene shows low constraint against loss-of-function variants (pLI near 0), suggesting tolerance to complete gene loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.731 OMIM phenotype

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

24 unique Pathogenic / Likely Pathogenic· 334 VUS of 849 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE?0.47 (0.31–0.73)

0≤0.351.4

Missense OE?1.14 (1.07–1.23)

0≤0.61.4

Synonymous OE?1.44

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDVL1-related Robinow syndromeGOFAD

This gene — mechanism propensity

0.80top 25%

GOF

0.7126th %ile

LOF

0.4037th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-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

LOF100% of P/LP variants are LoF

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.1

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.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25817016 ↗

ClinVar Variant Classifications

849 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic9

VUS334

Likely Benign339

Benign86

Conflicting53

Pathogenic

Likely Pathogenic

334

VUS

339

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	0	0	0	15
Likely Pathogenic	9	0	0	0	9
VUS	20	295	15	4	334
Likely Benign	2	45	115	177	339
Benign	1	19	47	19	86
Conflicting	—				53
Total	47	359	177	200	836

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

131 pathogenic / likely-pathogenic (of 152) ClinVar copy-number / structural variants overlap DVL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →