ADAMTS19

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 19, 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 motif) protein family. Members of the family 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 protein encoded by this gene has high sequence similarity to the protein encoded by ADAMTS16, another family member. [provided by RefSeq, Jul 2008]

MANE transcript

NM_133638.6

Inheritance

ClinVar variants

P:12U:182B:16

Top phenotype

Cardiac valvular dysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr5:129,460,281-129,738,683

External References & Databases

Ensembl (ENSG00000145808)

Transcript & Mutation Effects

hg38 • Region Span ~278.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiac valvular dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859572

Submitter: PanelApp Australia

cardiac valvular dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859572

Submitter: G2P

cardiac valvular dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859572

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005453

Submitter: ClinGen

*ADAMTS19* was first reported in relation to autosomal recessive congenital heart disease in 2020 (Massadeh, Salam et al., PMID:32323311). Four loss-of-function variants identified in four probands in two publications (PMID:32323311,31844321)) are included in this curation. The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by an animal model. (PMID:31844321) In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on July 8th, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Cardiac valvular dysplasia 2AR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The condition can involve multiple types of cardiovascular anomalies, and awareness may allow early management

Refs: 31844321; 32323311

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS19 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 174

not providedTotal: 17

Cardiac valvular dysplasia 2Total: 11

ADAMTS19-related disorderTotal: 8

not specifiedTotal: 3

ADAMTS19-associated congenital heartdefectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_133638.6. 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				6 clinvar	1 clinvar	7
missense			178 clinvar	8 clinvar	1 clinvar	187
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss						0
frameshift	2 clinvar	3 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	1 clinvar			4
Total	7	5	182	14	2	210

Highest pathogenic variant AF is 0.000006934111

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_133638.6	RefSeq	NP_598377.4	23	MANE Select
ENST00000274487.9	Ensembl	ENSP00000274487.5	23	MANE Select
ENST00000502709.1	Ensembl	ENSP00000422491.1	3	Standard
ENST00000505791.5	Ensembl	ENSP00000423537.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
O-glycosylation of TSR domain-containing proteins
O-linked glycosylation

Biological Process

proteolysis

Molecular Function

metalloendopeptidase activity
metal ion binding

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274487
Coding exons: 23
Length: 278419
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 125748
p: 0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.10	451	595	0.758	0.0000291	7814
Missense (PolyPhen)		122	230.94	0.52828		2815
Synonymous	-0.0872	206	204	1.01	0.00000999	2277
Loss of Function	4.54	24	62.9	0.382	0.00000344	768

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00027	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00024	0.00023	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.440
RVIS EVS: -0.55
RVIS percentile EVS: 19.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.256

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium