HOGA1

protein-coding

4-hydroxy-2-oxoglutarate aldolase 1

Gene summary

The authors of PMID:20797690 cloned this gene while searching for genes in a region of chromosome 10 linked to primary hyperoxalurea type III. They noted that even though the encoded protein has been described as a mitochondrial dihydrodipicolinate synthase-like enzyme, it shares little homology with E. coli dihydrodipicolinate synthase (Dhdps), particularly in the putative substrate-binding region. Moreover, neither lysine biosynthesis nor sialic acid metabolism, for which Dhdps is responsible, occurs in vertebrate mitochondria. They propose that this gene encodes mitochondrial 4-hydroxyl-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. This gene is predominantly expressed in the liver and kidney, and mutations in this gene are found in patients with primary hyperoxalurea type III. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Nov 2010]

Previous symbols:

C10orf65
DHDPSL

MANE transcript

NM_138413.4

Inheritance

AR, AD

ClinVar variants

P:160U:129B:144

Top phenotype

Hyperoxaluria, primary, type III

gnomAD constraint

pLI —, LoF o/e 1.24

Max pathogenic AF

—

Genomic locus

chr10:97,584,323-97,612,802

External References & Databases

Ensembl (ENSG00000241935)

Transcript & Mutation Effects

hg38 • Region Span ~28.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary hyperoxaluria type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: PanelApp Australia

primary hyperoxaluria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: Natera

primary hyperoxaluria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: Myriad Women's Health

primary hyperoxaluria type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: Labcorp Genetics (formerly Invitae)

primary hyperoxaluria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: ClinGen

HOGA1 was first reported in relation to autosomal recessive Primary Hyperoxaluria III (HP3) in 2010 (Belostotsky et al., PMID: 20797690). 17 variants (missense, in-frame indel, splicing, frameshift, nonsense) that have been reported in 16 probands in 5 publications (PMIDs: 20797690, 21896830, 22391140, 28711958, 31123811) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, The mechanism of disease appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression-level evidence; GTEx and Humphrey’s Lab expression data). A mouse model was evaluated, but was not scored as the mice lacked urinary oxalate excretion, a key part of the human phenotype. In summary, there is definitive evidence supporting the relationship between HOGA1 and autosomal recessive HP3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 5/30/2024 (SOP Version 10).

primary hyperoxaluria type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013327

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hyperoxaluria, primary, type IIIAD/AR

Manifestation: Biochemical; Renal

Intervention: Renal

Rationale: Increased fluid intake in order to promote hydration as well as medical therapy (eg, neutral phosphate therapy, citrate medications, thiazides) may be beneficial

Refs: 20797690; 21896830; 22781098; 22688746; 22391140

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HOGA1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 357

Primary hyperoxaluria type 3Total: 266

Inborn genetic diseasesTotal: 48

not specifiedTotal: 28

HOGA1-related disorderTotal: 17

HOGA1-related disordersTotal: 11

Glycogen storage disease due to muscle and heart glycogen synthase deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138413.4. 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	7 clinvar	134 clinvar	1 clinvar	143
missense	7 clinvar	63 clinvar	122 clinvar	9 clinvar		201
nonsense	13 clinvar	10 clinvar				23
start loss	2 clinvar	1 clinvar				3
frameshift	18 clinvar	24 clinvar				42
splice donor/acceptor (+/-2bp)	1 clinvar	20 clinvar				21
Total	41	119	129	143	1	433

Highest pathogenic variant AF is 0.0022654484

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138413.4	RefSeq	NP_612422.2	7	MANE Select
ENST00000370646.9	Ensembl	ENSP00000359680.4	7	MANE Select
NM_001134670.2	RefSeq	NP_001128142.1	3	Standard
ENST00000370642.4	Ensembl	ENSP00000359676.4	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
Metabolism of amino acids and derivatives
Metabolism
4-hydroxyproline degradation

Biological Process

glyoxylate catabolic process
4-hydroxyproline catabolic process
oxalate metabolic process
pyruvate biosynthetic process
glyoxylate metabolic process

Molecular Function

protein binding
4-hydroxy-2-oxoglutarate aldolase activity
protein homodimerization activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370646
Coding exons: 7
Length: 28480
Individuals with no LoFs: 125677
Homozygous LoFs: 1
Heterozygous LoFs: 70
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.279	217	206	1.05	0.0000128	2115
Missense (PolyPhen)		81	77.025	1.0516		787
Synonymous	0.710	75	83.2	0.901	0.00000538	686
Loss of Function	-0.874	19	15.3	1.24	8.32e-7	155

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00094	0.00092	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00043	0.00039	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the final step in the metabolic pathway of hydroxyproline. {ECO:0000269|PubMed:20797690, ECO:0000269|PubMed:21998747}.;
Disease: DISEASE: Hyperoxaluria primary 3 (HP3) [MIM:613616]: A disorder phenotypically similar to hyperoxaluria type 1 and type 2. It is characterized by increase in urinary oxalate excretion and mild glycolic aciduria. Clinical manifestations include calcium oxalate urolithiasis, hematuria, pain, and/or urinary tract infection. {ECO:0000269|PubMed:20797690}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.146

Intolerance Scores

RVIS EVS: -1
RVIS percentile EVS: 8.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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