AASS

protein-coding

aminoadipate-semialdehyde synthase

Gene summary

This gene encodes a bifunctional enzyme that catalyzes the first two steps in the mammalian lysine degradation pathway. The N-terminal and the C-terminal portions of this enzyme contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Mutations in this gene are associated with familial hyperlysinemia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005763.4

Inheritance

ClinVar variants

P:26U:164B:53

Top phenotype

Hyperlysinemia, type I

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr7:122,064,583-122,144,308

External References & Databases

Ensembl (ENSG00000008311)

Transcript & Mutation Effects

hg38 • Region Span ~79.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperlysinemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: Ambry Genetics

hyperlysinemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: ClinGen

*AASS* was first reported in relation to autosomal recessive hyperlysinemia in 2000 (Sacksteder KA, et al., 2000, PMID: 10775527). At least 13 unique variants (e.g. missense, nonsense, frameshift, large deletion, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 23890588, 10775527, 27604308, 23570448). Variants in this gene segregated with disease in 2 additional family members. Of note, this gene has also been implicated in Saccharopinuria but no putative causal variants have been identified in patients. This gene-disease relationship is supported by its biochemical function in lysine catabolism and a knock-in mouse model which recapitulates the human phenotype of hyperlysinemia (PMID: 35135854). In summary, *AASS* is definitively associated with autosomal recessive hyperlysinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 06/29/2020. It was re-evaluated on 10/14/2022. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new mouse model (PMIDs: 35135854).

hyperlysinemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: PanelApp Australia

hyperlysinemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: Orphanet

hyperlysinemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: G2P

hyperlysinemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009388

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperlysinemia, type IAR

Manifestation: Biochemical

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

Comments: Other than increased serum lysine, the evidence of a common phenotype is unclear, and there does not appear to be evidence that measures such as protein restriction or other metabolic treatments are effective

Refs: 14209691; 5796356; 5557172; 934735; 10775527; 23570448

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AASS variants in ClinVar

9 Conditions Cataloged

not providedTotal: 151

Inborn genetic diseasesTotal: 109

HyperlysinemiaTotal: 28

not specifiedTotal: 14

AASS-related disorderTotal: 6

HYPERLYSINEMIA, TYPE ITotal: 5

SaccharopinuriaTotal: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005763.4. 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	39 clinvar	1 clinvar	44
missense	2 clinvar	2 clinvar	153 clinvar	10 clinvar	3 clinvar	170
nonsense	4 clinvar	3 clinvar				7
start loss		1 clinvar				1
frameshift	2 clinvar	5 clinvar				7
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	7 clinvar			14
Total	9	17	164	49	4	243

Highest pathogenic variant AF is 0.000026032014

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005763.4	RefSeq	NP_005754.2	23	MANE Select
ENST00000417368.7	Ensembl	ENSP00000403768.2	23	MANE Select
ENST00000358954.6	Ensembl	ENSP00000351834.2	19	Standard
ENST00000393376.5	Ensembl	ENSP00000377040.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Lysine Degradation
Hyperlysinemia I, Familial
2-aminoadipic 2-oxoadipic aciduria
Pyridoxine dependency with seizures

Biological Process

lysine catabolic process
lysine biosynthetic process via aminoadipic acid
L-lysine catabolic process to acetyl-CoA via saccharopine
protein tetramerization
oxidation-reduction process

Molecular Function

saccharopine dehydrogenase activity
saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393376
Coding exons: 23
Length: 68634
Individuals with no LoFs: 125673
Homozygous LoFs: 0
Heterozygous LoFs: 75
Defined: 125748
p: 0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.882	449	505	0.889	0.0000267	6058
Missense (PolyPhen)		157	194.48	0.80729		2270
Synonymous	0.410	172	179	0.961	0.00000960	1785
Loss of Function	2.58	26	44.6	0.583	0.00000192	635

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00054	0.00054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00059	0.00059	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Bifunctional enzyme that catalyzes the first two steps in lysine degradation. The N-terminal and the C-terminal contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively.;
Disease: DISEASE: Hyperlysinemia, 1 (HYPLYS1) [MIM:238700]: An autosomal recessive metabolic condition with variable clinical features. Some patients present with non-specific seizures, hypotonia, or mildly delayed psychomotor development, and increased serum lysine and pipecolic acid on laboratory analysis. However, about half of the probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant. {ECO:0000269|PubMed:10775527}. Note=The disease is caused by mutations affecting the gene represented in this entry. In hyperlysinemia 1, both enzymatic functions of AASS are defective and patients have increased serum lysine and possibly increased saccharopine. Some individuals, however, retain significant amounts of lysine-ketoglutarate reductase and present with saccharopinuria, a metabolic condition with few, if any, clinical manifestations. {ECO:0000305|PubMed:463877}.; DISEASE: 2,4-dienoyl-CoA reductase deficiency (DECRD) [MIM:616034]: A rare, autosomal recessive, inborn error of polyunsaturated fatty acids and lysine metabolism, resulting in mitochondrial dysfunction. Affected individuals have a severe encephalopathy with neurologic and metabolic abnormalities beginning in early infancy. Laboratory studies show increased C10:2 carnitine levels and hyperlysinemia. {ECO:0000269|PubMed:24847004}. Note=The protein represented in this entry is involved in disease pathogenesis. A selective decrease in mitochondrial NADP(H) levels due to NADK2 mutations causes a deficiency of NADPH-dependent mitochondrial enzymes, such as DECR1 and AASS. {ECO:0000269|PubMed:24847004}.;

Intolerance Scores

LoFtool: 0.355
RVIS EVS: -0.91
RVIS percentile EVS: 10.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

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