TLL1

protein-coding

tolloid like 1, the group of Astacins

Gene summary

This gene encodes an astacin-like, zinc-dependent, metalloprotease that belongs to the peptidase M12A family. This protease processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Studies in mice suggest that this gene plays multiple roles in the development of mammalian heart, and is essential for the formation of the interventricular septum. Allelic variants of this gene are associated with atrial septal defect type 6. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

MANE transcript

NM_012464.5

Inheritance

ClinVar variants

P:4U:152B:41

Top phenotype

Atrial septal defect 6

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr4:165,873,237-166,104,457

External References & Databases

Ensembl (ENSG00000038295)

Transcript & Mutation Effects

hg38 • Region Span ~231.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*TLL1* was first reported in relation to autosomal dominant congenital heart disease in 2009 (Stanczak et al. 2009, PMID: 18830233). Four variants (missense, frameshift) that have been reported in 4 probands in 3 publications (PMID: 18830233, 30293987, 31570783) are included in this curation. There are more variants reported in individuals with CHD in 6 publications, all of which were not scored due to a high minor allele frequency (>0.00001) in gnomAD v.4, being located in the 5’ untranslated region of the gene, the proband having a syndromic phenotype, and/or the proband having an unclear phenotype (PMID: 18830233, 27418595, 28358424, 30293987, 32552793, 34328347). The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by expression data in mouse embryos (PMID: 10331975), protein interaction data (PMID: 19366374, 26744331), and a mouse model showing heart defects (PMID: 10331975). In summary, there is limited evidence supporting the relationship between *TLL1* and autosomal dominant congenital heart disease. 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 the meeting date May 13th, 2024 (SOP Version 10).

atrial septal defect 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013123

Submitter: G2P

mitral valve prolapseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0004910

Submitter: Ambry Genetics

atrial septal defect 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013123

Submitter: PanelApp Australia

atrial septal defect 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013123

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Atrial septal defect 6AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: In addition to managing congenital cardiac malformations, surveillance for (eg, including electrocardiogram) and treatment of accompanying arrhythmias may be effective

Comments: The condition can include arrhthymias as well as frank congenital cardiac malformations

Refs: 18830233

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLL1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 165

not providedTotal: 28

TLL1-related disorderTotal: 24

Atrial septal defect 6Total: 22

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012464.5. 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			1 clinvar	24 clinvar	1 clinvar	26
missense	2 clinvar	1 clinvar	147 clinvar	14 clinvar	2 clinvar	166
nonsense			3 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	3	1	152	38	3	197

Highest pathogenic variant AF is 0.000002052607

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012464.5	RefSeq	NP_036596.3	21	MANE Select
ENST00000061240.7	Ensembl	ENSP00000061240.2	21	MANE Select
NM_001204760.2	RefSeq	NP_001191689.1	10	Standard
ENST00000504560.5	Ensembl	ENSP00000421732.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tll1	Danio rerio	Structure: post-vent region Quality: bifurcated abnormal

Gene / Model

Organism

Observed Phenotype

tll1

Danio rerio

Structure: post-vent region

Quality: bifurcated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Crosslinking of collagen fibrils
Assembly of collagen fibrils and other multimeric structures
Collagen biosynthesis and modifying enzymes
Collagen formation
Extracellular matrix organization

Biological Process

skeletal system development
proteolysis
extracellular matrix disassembly
cell differentiation

Molecular Function

metalloendopeptidase activity
serine-type endopeptidase activity
calcium ion binding
zinc ion binding

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000061240
Coding exons: 21
Length: 230638
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.940	484	546	0.887	0.0000289	6687
Missense (PolyPhen)		112	171.67	0.65242		2115
Synonymous	-0.942	208	191	1.09	0.0000103	1818
Loss of Function	5.44	14	59.1	0.237	0.00000347	685

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000097	0.000088	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.;
Disease: DISEASE: Atrial septal defect 6 (ASD6) [MIM:613087]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. {ECO:0000269|PubMed:18830233}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.137

Intolerance Scores

LoFtool: 0.461
RVIS EVS: -0.93
RVIS percentile EVS: 9.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.397

Gene Damage Prediction

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