Atrial septal defect 6

Summary

Atrial septal defect 6 (MONDO:0013123) is a disease caused by TLL1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TLL1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial septal defect 6
Mondo ID	MONDO:0013123
MeSH	C567764
OMIM	613087
DOID	DOID:0110111
UMLS	C2751315
MedGen	414348
GARD	0024900
Is cancer (heuristic)	no

Also known as: ASD6 · atrial heart septal defect caused by mutation in TLL1 · atrial heart septal defect type 6 · atrial septal defect 6 · atrial septal defect type 6 · TLL1 atrial heart septal defect

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › atrial septal defect › atrial septal defect 6

Related subtypes (14): Lutembacher syndrome, atrial septal defect 1, atrial septal defect 7, atrial septal defect 2, atrial septal defect 4, atrial septal defect 5, atrial septal defect 3, atrial septal defect 8, atrial septal defect 9, atrial septal defect, ostium secundum type, atrial septal defect, coronary sinus type, atrial septal defect, sinus venosus type, atrial septal defect, ostium primum type, patent foramen ovale

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
690359	NM_012464.5(TLL1):c.1379-2A>G	LOC126807212	Pathogenic	criteria provided, single submitter
4074	NM_012464.5(TLL1):c.544A>C (p.Met182Leu)	TLL1	Pathogenic	no assertion criteria provided
4076	NM_012464.5(TLL1):c.1885A>G (p.Ile629Val)	TLL1	Pathogenic	no assertion criteria provided
4277527	NM_012464.5(TLL1):c.605A>G (p.Tyr202Cys)	TLL1	Likely pathogenic	criteria provided, single submitter
2437104	NM_012464.5(TLL1):c.2783G>A (p.Arg928Gln)	TLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2581026	NM_012464.5(TLL1):c.985C>T (p.Arg329Ter)	LOC123493235	Uncertain significance	criteria provided, single submitter
1678575	NM_012464.5(TLL1):c.1414C>T (p.Gln472Ter)	LOC126807212	Uncertain significance	criteria provided, single submitter
2437105	NM_012464.5(TLL1):c.1399C>T (p.Arg467Cys)	LOC126807212	Uncertain significance	criteria provided, single submitter
2498219	NM_012464.5(TLL1):c.1472A>G (p.Lys491Arg)	LOC126807212	Uncertain significance	criteria provided, single submitter
1325537	NM_012464.5(TLL1):c.2993T>A (p.Ile998Lys)	TLL1	Uncertain significance	criteria provided, single submitter
1806097	NM_012464.5(TLL1):c.1729G>A (p.Glu577Lys)	TLL1	Uncertain significance	criteria provided, single submitter
1806100	NM_012464.5(TLL1):c.3015T>A (p.Tyr1005Ter)	TLL1	Uncertain significance	criteria provided, single submitter
2437103	NM_012464.5(TLL1):c.2540G>A (p.Arg847Gln)	TLL1	Uncertain significance	criteria provided, single submitter
2437106	NM_012464.5(TLL1):c.1669G>C (p.Val557Leu)	TLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437107	NM_012464.5(TLL1):c.2044C>A (p.Leu682Ile)	TLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2523352	NM_012464.5(TLL1):c.1955C>G (p.Thr652Ser)	TLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064798	NM_012464.5(TLL1):c.629G>A (p.Cys210Tyr)	TLL1	Uncertain significance	criteria provided, single submitter
3892654	NM_012464.5(TLL1):c.2183T>C (p.Phe728Ser)	TLL1	Uncertain significance	criteria provided, single submitter
4075	NM_012464.5(TLL1):c.713T>C (p.Val238Ala)	TLL1	Uncertain significance	criteria provided, single submitter
4277921	NM_012464.5(TLL1):c.1856G>T (p.Gly619Val)	TLL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TLL1	Strong	Autosomal dominant	atrial septal defect 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TLL1	Orphanet:99103	Atrial septal defect, ostium secundum type
TLL1	Orphanet:99106	Atrial septal defect, ostium primum type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TLL1	HGNC:11843	ENSG00000038295	O43897	Tolloid-like protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TLL1	Tolloid-like protein 1	Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TLL1	Protease	yes		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
primordial germ cell in gonad	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TLL1	162	broad	marker	secondary oocyte, buccal mucosa cell, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TLL1	855

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TLL1	O43897	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	1	761.3×	0.004	TLL1
Crosslinking of collagen fibrils	1	571.0×	0.004	TLL1
Collagen biosynthesis and modifying enzymes	1	170.4×	0.008	TLL1
Degradation of the extracellular matrix	1	117.7×	0.008	TLL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dorsal/ventral pattern formation	1	421.3×	0.010	TLL1
collagen fibril organization	1	224.7×	0.010	TLL1
protein processing	1	170.2×	0.010	TLL1
skeletal system development	1	125.8×	0.010	TLL1
cell differentiation	1	29.1×	0.034	TLL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TLL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TLL1	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TLL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TLL1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.