Familial visceral amyloidosis

Summary

Familial visceral amyloidosis (MONDO:0007099) is a disease caused by variants in APOA1, FGA, and LYZ, with 5 cohort genes. The dominant Reactome pathway is Amyloid fiber formation (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: APOA1 (GenCC Strong), FGA (GenCC Strong), LYZ (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 218
• Phenotypes (HPO): 43

Clinical features

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000093	Proteinuria	Very frequent (80-99%)
HP:0000112	Nephropathy	Very frequent (80-99%)
HP:0032613	Renal interstitial amyloid deposits	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001970	Tubulointerstitial nephritis	Frequent (30-79%)
HP:0003259	Elevated circulating creatinine concentration	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0012213	Decreased glomerular filtration rate	Frequent (30-79%)
HP:0012591	Abnormal urinary electrolyte concentration	Frequent (30-79%)
HP:0000017	Nocturia	Occasional (5-29%)
HP:0000092	Renal tubular atrophy	Occasional (5-29%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000967	Petechiae	Occasional (5-29%)
HP:0000979	Purpura	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0002733	Abnormality of the lymph nodes	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003233	Decreased HDL cholesterol concentration	Occasional (5-29%)
HP:0003565	Elevated erythrocyte sedimentation rate	Occasional (5-29%)
HP:0005214	Intestinal obstruction	Occasional (5-29%)
HP:0005576	Tubulointerstitial fibrosis	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0031368	Intestinal perforation	Occasional (5-29%)
HP:0031799	Decreased apolipoprotein AI level	Occasional (5-29%)
HP:0410281	Dyspepsia	Occasional (5-29%)
HP:0000035	Abnormal testis morphology	Very rare (<1-4%)
HP:0000135	Hypogonadism	Very rare (<1-4%)
HP:0000798	Oligozoospermia	Very rare (<1-4%)
HP:0003251	Male infertility	Very rare (<1-4%)
HP:0008720	Primary testicular failure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial visceral amyloidosis
Mondo ID	MONDO:0007099
MeSH	C538249
OMIM	105200
Orphanet	85450
DOID	DOID:0050636
SNOMED CT	66451004
UMLS	C0268389
MedGen	82799
GARD	0008282
Is cancer (heuristic)	no

Also known as: amyloidosis familial renal · amyloidosis familial visceral · amyloidosis systemic nonneuropathic · amyloidosis VIII · amyloidosis, 3 or more types · amyloidosis, familial renal · amyloidosis, Ostertag type · amyloidosis, renal · familial amyloid nephropathy · familial renal amyloidosis · German type amyloidosis · hereditary amyloid nephropathy · hereditary amyloidosis with primary renal involement · hereditary renal amyloidosis · Ostertag type amyloidosis

Data availability: 218 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hereditary amyloidosis › familial visceral amyloidosis

Related subtypes (8): cerebral amyloid angiopathy, Finnish type amyloidosis, familial amyloid neuropathy, familial primary localized cutaneous amyloidosis, variant ABeta2M amyloidosis, ITM2B amyloidosis, pulmonary amyloidosis, APP-related brain and vascular amyloidosis

Subtypes (4): apolipoprotein A-II amyloidosis, AApoAI amyloidosis, ALys amyloidosis, AFib amyloidosis

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

218 retrieved; paginated sample, class counts are floors:

115 uncertain significance, 25 conflicting classifications of pathogenicity, 23 benign, 15 benign/likely benign, 12 likely benign, 10 pathogenic/likely pathogenic, 9 likely pathogenic, 9 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17917	NM_000039.3(APOA1):c.148G>C (p.Gly50Arg)	APOA1	Pathogenic	criteria provided, multiple submitters, no conflicts
565272	NM_000039.3(APOA1):c.532_533dup (p.His179fs)	APOA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31907	NM_004048.4(B2M):c.286G>A (p.Asp96Asn)	B2M	Pathogenic	criteria provided, single submitter
1322896	NM_021871.4(FGA):c.364+1G>A	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322897	NM_021871.4(FGA):c.1653del (p.Gly552fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16404	NM_021871.4(FGA):c.104G>A (p.Arg35His)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
16409	NM_021871.4(FGA):c.1622del (p.Val541fs)	FGA	Pathogenic	no assertion criteria provided
16410	NM_021871.4(FGA):c.1634A>T (p.Glu545Val)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16413	NM_021871.4(FGA):c.1629del (p.Thr544fs)	FGA	Pathogenic	no assertion criteria provided
16415	NM_021871.4(FGA):c.510+1G>T	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684487	NM_021871.4(FGA):c.1055del (p.Pro352fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803153	NM_021871.4(FGA):c.713del (p.Lys238fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3356488	NM_021871.4(FGA):c.1541del (p.Pro514fs)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
402230	NM_021871.4(FGA):c.502C>T (p.Arg168Ter)	FGA	Pathogenic	criteria provided, multiple submitters, no conflicts
627216	NM_021871.4(FGA):c.117del (p.Val40fs)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
627406	NM_021871.4(FGA):c.922C>T (p.Arg308Ter)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632435	NM_021871.4(FGA):c.532C>T (p.Arg178Ter)	FGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14376	NM_000239.3(LYZ):c.244T>C (p.Trp82Arg)	LYZ	Pathogenic	criteria provided, single submitter
14378	NM_000239.3(LYZ):c.244T>A (p.Trp82Arg)	LYZ	Pathogenic	criteria provided, single submitter
2572647	NM_000039.3(APOA1):c.126C>G (p.Tyr42Ter)	APOA1-AS	Likely pathogenic	criteria provided, single submitter
217869	NM_004048.4(B2M):c.67+1G>T	B2M	Likely pathogenic	criteria provided, single submitter
1333679	NM_021871.4(FGA):c.1690_1699dup (p.Ile567fs)	FGA	Likely pathogenic	criteria provided, single submitter
16411	NM_000508.3(FGA):c.1717C>T (p.Arg573Cys)	FGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683308	NM_021871.4(FGA):c.1452del (p.Ser485fs)	FGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3380987	NM_021871.4(FGA):c.1736dup (p.Tyr579Ter)	FGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3590320	NM_021871.4(FGA):c.1339del (p.Glu447fs)	FGA	Likely pathogenic	criteria provided, single submitter
3590341	NM_021871.4(FGA):c.607C>T (p.Gln203Ter)	FGA	Likely pathogenic	criteria provided, single submitter
3590347	NM_021871.4(FGA):c.294_296del (p.Asn99del)	FGA	Likely pathogenic	criteria provided, single submitter
302502	NM_000039.3(APOA1):c.562G>T (p.Ala188Ser)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302503	NM_000039.3(APOA1):c.498C>A (p.Ser166Arg)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 10 · 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
APOA1	Strong	Autosomal dominant	familial visceral amyloidosis	7
B2M	Strong	Autosomal dominant	variant ABeta2M amyloidosis	6
FGA	Strong	Autosomal dominant	familial visceral amyloidosis	14
LYZ	Strong	Autosomal dominant	familial visceral amyloidosis	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGA	Orphanet:101041	Familial hypofibrinogenemia
FGA	Orphanet:248408	Familial hypodysfibrinogenemia
FGA	Orphanet:93562	AFib amyloidosis
FGA	Orphanet:98880	Familial afibrinogenemia
FGA	Orphanet:98881	Familial dysfibrinogenemia
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis
LYZ	Orphanet:93561	ALys amyloidosis
B2M	Orphanet:314652	Variant ABeta2M amyloidosis
B2M	Orphanet:34592	Immunodeficiency by defective expression of MHC class I

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGA	HGNC:3661	ENSG00000171560	P02671	Fibrinogen alpha chain	gencc,clinvar
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	gencc,clinvar
LYZ	HGNC:6740	ENSG00000090382	P61626	Lysozyme C	gencc,clinvar
B2M	HGNC:914	ENSG00000166710	P61769	Beta-2-microglobulin	gencc,clinvar
APOA1-AS	HGNC:40079	ENSG00000235910		APOA1 antisense RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGA	Fibrinogen alpha chain	Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix.
APOA1	Apolipoprotein A-I	Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT).
LYZ	Lysozyme C	Lysozymes have primarily a bacteriolytic function; those in tissues and body fluids are associated with the monocyte-macrophage system and enhance the activity of immunoagents.
B2M	Beta-2-microglobulin	Component of the class I major histocompatibility complex (MHC).

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Antibody/Immunoglobulin	1	5.8×	0.480
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGA	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_coil_dom, Fibrinogen_a/b/g_C_1
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
LYZ	Enzyme (other)	yes	3.2.1.17	Glyco_hydro_22_lys, Glyco_hydro_22, Glyco_hydro_22_CS
B2M	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
APOA1-AS	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
leukocyte	2
monocyte	2
islet of Langerhans	1
jejunal mucosa	1
mononuclear cell	1
granulocyte	1
colonic epithelium	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGA	153	tissue_specific	marker	right lobe of liver, liver, islet of Langerhans
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver
LYZ	270	broad	marker	monocyte, leukocyte, mononuclear cell
B2M	134	ubiquitous	marker	granulocyte, monocyte, leukocyte
APOA1-AS	131		marker	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOA1	3,608
FGA	2,327
B2M	415
LYZ	258
APOA1-AS	0

Intra-cohort edges

A	B	Sources
APOA1	FGA	biogrid_interaction, intact

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
B2M	P61769	1,226
LYZ	P61626	215
FGA	P02671	39
APOA1	P02647	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 92. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amyloid fiber formation	4	102.9×	8e-07	FGA, APOA1, LYZ, B2M
Defective ABCA1 causes TGD	1	1427.5×	0.012	APOA1
ER-Phagosome pathway	2	64.9×	0.012	FGA, B2M
Post-translational protein phosphorylation	2	50.1×	0.012	FGA, APOA1
Platelet degranulation	2	43.9×	0.012	FGA, APOA1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	43.3×	0.012	FGA, APOA1
Aggregated β-amyloid interacts with fibrinogen	1	713.8×	0.018	FGA
HDL clearance	1	571.0×	0.020	APOA1
Modulation by Mtb of host immune system	1	407.9×	0.020	B2M
HDL assembly	1	356.9×	0.020	APOA1
Nef mediated downregulation of MHC class I complex cell surface expression	1	285.5×	0.020	B2M
Chylomicron assembly	1	285.5×	0.020	APOA1
Chylomicron remodeling	1	285.5×	0.020	APOA1
HDL remodeling	1	285.5×	0.020	APOA1
Infection with Mycobacterium tuberculosis	1	285.5×	0.020	B2M
Endosomal/Vacuolar pathway	1	259.6×	0.020	B2M
Scavenging by Class B Receptors	1	259.6×	0.020	APOA1
Metabolism of proteins	3	9.3×	0.020	APOA1, LYZ, B2M
Scavenging of heme from plasma	1	219.6×	0.021	APOA1
Fibrin formation	1	219.6×	0.021	FGA
p130Cas linkage to MAPK signaling for integrins	1	190.3×	0.022	FGA
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	178.4×	0.022	FGA
Plasma lipoprotein assembly	1	178.4×	0.022	APOA1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	158.6×	0.022	B2M
The role of Nef in HIV-1 replication and disease pathogenesis	1	158.6×	0.022	B2M
ABC transporters in lipid homeostasis	1	150.3×	0.022	APOA1
Scavenging by Class A Receptors	1	150.3×	0.022	APOA1
MyD88 deficiency (TLR2/4)	1	150.3×	0.022	FGA
IRAK4 deficiency (TLR2/4)	1	142.8×	0.022	FGA
Binding and Uptake of Ligands by Scavenger Receptors	1	135.9×	0.022	APOA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of substrate adhesion-dependent cell spreading	2	187.2×	0.004	FGA, APOA1
negative regulation of iron ion transport	1	4213.0×	0.006	B2M
antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent	1	2106.5×	0.006	B2M
regulation of iron ion transport	1	2106.5×	0.006	B2M
cellular response to iron(III) ion	1	2106.5×	0.006	B2M
blood coagulation, common pathway	1	2106.5×	0.006	FGA
negative regulation of forebrain neuron differentiation	1	2106.5×	0.006	B2M
protein oxidation	1	1404.3×	0.006	APOA1
peptidyl-methionine modification	1	1404.3×	0.006	APOA1
regulation of intestinal cholesterol absorption	1	1053.2×	0.006	APOA1
positive regulation of phospholipid efflux	1	1053.2×	0.006	APOA1
acylglycerol homeostasis	1	842.6×	0.006	APOA1
negative regulation of cell adhesion molecule production	1	842.6×	0.006	APOA1
cellular response to lipoprotein particle stimulus	1	842.6×	0.006	APOA1
peptide antigen assembly with MHC class I protein complex	1	702.2×	0.006	B2M
negative regulation of cytokine production involved in immune response	1	702.2×	0.006	APOA1
glucocorticoid metabolic process	1	702.2×	0.006	APOA1
negative regulation of very-low-density lipoprotein particle remodeling	1	702.2×	0.006	APOA1
lipoprotein biosynthetic process	1	702.2×	0.006	APOA1
induction of bacterial agglutination	1	702.2×	0.006	FGA
regulation of erythrocyte differentiation	1	702.2×	0.006	B2M
vitamin transport	1	702.2×	0.006	APOA1
negative regulation of response to cytokine stimulus	1	702.2×	0.006	APOA1
cholesterol import	1	702.2×	0.006	APOA1
high-density lipoprotein particle clearance	1	601.9×	0.007	APOA1
cellular response to iron ion	1	601.9×	0.007	B2M
response to molecule of bacterial origin	1	526.6×	0.007	B2M
antigen processing and presentation of endogenous peptide antigen via MHC class I	1	526.6×	0.007	B2M
cellular response to nicotine	1	526.6×	0.007	B2M
positive regulation of cholesterol metabolic process	1	526.6×	0.007	APOA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGA	0	0
APOA1	0	0
LYZ	0	0
B2M	0	0
APOA1-AS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
B2M	5	Binding:5
APOA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LYZ	3.2.1.17	lysozyme

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	LYZ, B2M
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FGA, APOA1, APOA1-AS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGA	0	—
APOA1	2	—
LYZ	0	—
B2M	5	—
APOA1-AS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.