TIMP3

Chr 22AD

TIMP metallopeptidase inhibitor 3

Also known as: HSMRK222, K222, K222TA2, SFD

NCBI Gene: 7078 ENSG00000100234 UniProt: P35625 OMIM: 188826

This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.531 OMIM phenotype

Clinical Summary— TIMP3

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Gene-Disease Validity (ClinGen)

Sorsby fundus dystrophy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 141 VUS of 283 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TIMP3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.630

Z-score 2.64

OE 0.17 (0.07–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.83Z-score

OE missense 0.54 (0.44–0.66)

68 obs / 125.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.53)

0≤0.351.4

Missense OE?0.54 (0.44–0.66)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 11.8Missense obs/exp: 68 / 125.7Syn Z: -0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTIMP3-related Sorsby fundus dystrophyLOFAD

This gene — mechanism propensity

0.4090th %ile

GOF

0.4874th %ile

LOF

0.51top 25%

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

LOF1 literature citation

DN1 literature citation

Literature Evidence

DNOur data indicate that TIMP3 is a dominant negative regulator of angiogenesis in cutaneous melanoma and gene silencing by promoter methylation is associated with poor outcome.1

LOFWe propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.2

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

References

ClinVar Variant Classifications

283 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic5

VUS141

Likely Benign73

Benign40

Conflicting10

Pathogenic

Likely Pathogenic

141

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	6	0	0	6
Likely Pathogenic	1	4	0	0	5
VUS	4	72	64	1	141
Likely Benign	0	2	26	45	73
Benign	0	2	33	5	40
Conflicting	—				10
Total	5	86	123	51	275

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap TIMP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →