ALDOA

protein-coding

aldolase, fructose-bisphosphate A, the group of Aldolases

Gene summary

This gene encodes a member of the class I fructose-bisphosphate aldolase protein family. The encoded protein is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Three aldolase isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Mutations in this gene have been associated with Glycogen Storage Disease XII, an autosomal recessive disorder associated with hemolytic anemia. Disruption of this gene also plays a role in the progression of multiple types of cancers. Related pseudogenes have been identified on chromosomes 3 and 10. [provided by RefSeq, Sep 2017]

MANE transcript

NM_001243177.4

Inheritance

ClinVar variants

P:13U:135B:96

Top phenotype

Glycogen storage disease XII

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr16:30,064,164-30,070,457

External References & Databases

Ensembl (ENSG00000149925)

Transcript & Mutation Effects

hg38 • Region Span ~6.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease due to aldolase A deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012747

Submitter: Orphanet

glycogen storage disease due to aldolase A deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012747

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease due to aldolase A deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012747

Submitter: G2P

glycogen storage disease due to aldolase A deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012747

Submitter: PanelApp Australia

glycogen storage disease due to aldolase A deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012747

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Glycogen storage disease XIIAR

Manifestation: Biochemical; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical; Hematologic; Renal

Rationale: Individuals can have rhabdomyolysis from stressors such as febrile illness, and appropriate precautions and management may be beneficial; Aldolase A deficiency is also asociated with hereditary hemolytic anemia, and transfusions and splenectomy have been described in treatment

Refs: 4788792; 7331996; 3688035; 2825199; 8598869; 14615364

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALDOA variants in ClinVar

7 Conditions Cataloged

HNSHA due to aldolase A deficiencyTotal: 267

not providedTotal: 57

not specifiedTotal: 33

ALDOA-related disorderTotal: 29

Inborn genetic diseasesTotal: 28

Glycogen storage diseaseTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001243177.4. 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			1 clinvar	90 clinvar	1 clinvar	92
missense	2 clinvar	3 clinvar	131 clinvar	4 clinvar	1 clinvar	141
nonsense	1 clinvar					1
start loss			1 clinvar			1
frameshift	3 clinvar	1 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)		3 clinvar				3
Total	6	7	135	94	2	244

Highest pathogenic variant AF is 0.000013166904

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001243177.4	RefSeq	NP_001230106.1	9	MANE Select
ENST00000642816.3	Ensembl	ENSP00000496166.1	9	MANE Select
NM_001127617.2	RefSeq	NP_001121089.1	8	Standard
NM_184041.5	RefSeq	NP_908930.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
aldoaa	Danio rerio	Structure: pigment cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

aldoaa

Danio rerio

Structure: pigment cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
Fructose and mannose metabolism - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
Pentose phosphate pathway - Homo sapiens (human)
Pentose Phosphate Pathway

Biological Process

platelet degranulation
fructose metabolic process
gluconeogenesis
glycolytic process
ATP biosynthetic process

Molecular Function

RNA binding
actin binding
fructose-bisphosphate aldolase activity
protein binding
cytoskeletal protein binding

Cellular Component

extracellular region
extracellular space
nucleus
cytosol
actin cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395248
Coding exons: 9
Length: 17368
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125747
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.259	235	246	0.954	0.0000161	2705
Missense (PolyPhen)		36	61.135	0.58886		817
Synonymous	-2.52	136	103	1.32	0.00000707	861
Loss of Function	2.36	8	19.1	0.418	0.00000101	220

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a key role in glycolysis and gluconeogenesis. In addition, may also function as scaffolding protein (By similarity). {ECO:0000250}.;
Disease: DISEASE: Glycogen storage disease 12 (GSD12) [MIM:611881]: A metabolic disorder associated with increased hepatic glycogen and hemolytic anemia. It may lead to myopathy with exercise intolerance and rhabdomyolysis. {ECO:0000269|PubMed:14615364, ECO:0000269|PubMed:14766013, ECO:0000269|PubMed:2229018, ECO:0000269|PubMed:2825199, ECO:0000269|PubMed:8598869}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.571

Intolerance Scores

LoFtool: 0.0383
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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