ADAMTS18

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 18, the group of ADAM metallopeptidases with thrombospondin type 1 motif

Gene summary

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protein, which may regulate hemostatic balance and function as a tumor suppressor. Mutations in this gene may be associated with microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) and cone-rod dystrophy in human patients. [provided by RefSeq, May 2016]

Previous symbols:

ADAMTS21

MANE transcript

NM_199355.4

Inheritance

ClinVar variants

P:68U:646B:397

Top phenotype

Microcornea, myopic chorioretinal atrophy, and telecanthus

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr16:77,247,813-77,435,034

External References & Databases

Ensembl (ENSG00000140873)

Transcript & Mutation Effects

hg38 • Region Span ~187.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcornea-myopic chorioretinal atrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014195

Submitter: Orphanet

microcornea-myopic chorioretinal atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014195

Submitter: ClinGen

ADAMTS18 was first reported in relation to autosomal recessive Microcornea-Myopic Chorioretinal Atrophy in 2013 (Aldahmesh, 23818446). This syndrome is characterized by novel ocular findings in addition to distinct facial features including telecanthus in some patients, wide nose or broad nasal tip and posterior rotation of the ears. Additional studies however were limited to phenotypes primarily involving visual function (23356391, 24874986). At least 8 variants (5 missense, 3 nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Case level data includes predicted null variants that have been reported in 4 probands in 2 publications (23818446, 24874986) and missense variants predicted to impact gene function reported in 5 probands (23818446, 24874986, 23356391). In the 8 families with variants in this gene, 7 variants segregated with disease in 6 additional affected family members. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by animal models, expression studies, in vivo functional assays in model organisms contributing to the experimental evidence scoring (2 pts.) (21862674, 23356391). Peluso et al. showed expression of ADAMTS18 from cDNA isolated from retina using RT-PCR with gene specific primers and confirmed by Sanger sequencing. As well as investigating expression in adult mice at P60 using In situ hybridization and found Adamts18 expressed in retinal ganglion cell layer, inner nuclear layer, and RPE. In vivo assays to determine the function of ADAMTS18 were performed in medaka fish using a light-induced photoreceptor degeneration assay and found that fish with translation-blocking morpholinos had reduced thicknes in the outer segments along with fewer Rhodopsin positive cells indicating photoreceptor cells loss indicative of retinal degeneration (Peluso, 23356391). These studies point to the role of ADAMTS18 in visual development and function. ● DEFINITIVE: In summary, there is strong evidence to support the relationship between ADAMTS18 and autosomal recessive Microcornea-Myopic Chorioretinal Atrophy

inherited retinal dystrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: Franklin by Genoox

A 30-year old male, displayed a severe early-onset retinal dystrophy accompanied by an autistic disorder underwent DNA examination which revealed homozygous missense variation, namely c.T3235‚Äâ>‚ÄâC (p.C1079R) in the ADAMTS18 gene. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568033/

microcornea-myopic chorioretinal atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014195

Submitter: G2P

microcornea-myopic chorioretinal atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014195

Submitter: Labcorp Genetics (formerly Invitae)

microcornea-myopic chorioretinal atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014195

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Microcornea, myopic chorioretinal atrophy, and telecanthusAR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21862674; 22686506; 23356391; 23818446

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS18 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 1166

Inborn genetic diseasesTotal: 250

not specifiedTotal: 179

ADAMTS18-related disorderTotal: 69

Microcornea-myopic chorioretinal atrophyTotal: 17

Retinal dystrophyTotal: 8

Leber congenital amaurosisTotal: 2

Retinitis pigmentosaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_199355.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	330 clinvar	6 clinvar	340
missense	1 clinvar	1 clinvar	632 clinvar	55 clinvar	6 clinvar	695
nonsense	26 clinvar	10 clinvar	4 clinvar			40
start loss						0
frameshift	11 clinvar	6 clinvar	3 clinvar			20
splice donor/acceptor (+/-2bp)		13 clinvar	3 clinvar			16
Total	38	30	646	385	12	1111

Highest pathogenic variant AF is 0.00023853868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_199355.4	RefSeq	NP_955387.1	23	MANE Select
ENST00000282849.10	Ensembl	ENSP00000282849.5	23	MANE Select
NM_001326358.2	RefSeq	NP_001313287.1	20	Standard
ENST00000449265.2	Ensembl	ENSP00000392540.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization
Degradation of the extracellular matrix
O-glycosylation of TSR domain-containing proteins

Biological Process

eye development
proteolysis
negative regulation of platelet aggregation

Molecular Function

metalloendopeptidase activity
metal ion binding

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282849
Coding exons: 23
Length: 187302
Individuals with no LoFs: 125601
Homozygous LoFs: 0
Heterozygous LoFs: 147
Defined: 125748
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-3.51	919	665	1.38	0.0000390	7914
Missense (PolyPhen)		270	256.49	1.0527		2927
Synonymous	-6.37	390	260	1.50	0.0000168	2336
Loss of Function	2.07	56	75.4	0.743	0.00000489	805

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00069	0.00069	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00080	0.00078	rare
South Asian	0.00059	0.00059	rare
Other	0.00082	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) [MIM:615458]: A ocular syndrome characterized by microcornea and myopic chorioretinal atrophy. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. In addition to ocular findings, some patients have telecanthus and posteriorly rotated ears. {ECO:0000269|PubMed:23818446}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0954

Intolerance Scores

LoFtool: 0.825
RVIS EVS: -0.09
RVIS percentile EVS: 47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.160

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High