L2HGDH

Summary

L2HGDH (L-2-hydroxyglutarate dehydrogenase, HGNC:20499) is a protein-coding gene on chromosome 14q21.3, encoding L-2-hydroxyglutarate dehydrogenase, mitochondrial (Q9H9P8).

This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability.

Source: NCBI Gene 79944 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 316 total — 32 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_024884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20499
Approved symbol	L2HGDH
Name	L-2-hydroxyglutarate dehydrogenase
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12618
Ensembl gene	ENSG00000087299
Ensembl biotype	protein_coding
OMIM	609584
Entrez	79944

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000261699, ENST00000267436, ENST00000421284, ENST00000554191, ENST00000555423, ENST00000555610, ENST00000556393, ENST00000889799, ENST00000889800, ENST00000889801

RefSeq mRNA: 8 — MANE Select: NM_024884 NM_001425212, NM_001425213, NM_001425214, NM_001425215, NM_001425216, NM_001425217, NM_001425218, NM_024884

CCDS: CCDS9698

Canonical transcript exons

ENST00000267436 — 10 exons

Exon	Start	End
ENSE00000656856	50294115	50294246
ENSE00000854639	50283871	50284033
ENSE00001001522	50278520	50278554
ENSE00001093851	50267753	50267910
ENSE00001093853	50265358	50265489
ENSE00001093855	50269163	50269330
ENSE00001174914	50242434	50247253
ENSE00001174937	50312011	50312229
ENSE00003507919	50302902	50303017
ENSE00003539142	50302017	50302168

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 80.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1660 / max 71.5713, expressed in 1422 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143146	3.4087	1290
143145	1.7573	843

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.70	gold quality
muscle of leg	UBERON:0001383	79.29	gold quality
gastrocnemius	UBERON:0001388	79.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.32	gold quality
adult mammalian kidney	UBERON:0000082	76.73	gold quality
muscle organ	UBERON:0001630	76.65	gold quality
islet of Langerhans	UBERON:0000006	76.64	gold quality
cortical plate	UBERON:0005343	76.32	gold quality
rectum	UBERON:0001052	74.98	gold quality
ventricular zone	UBERON:0003053	74.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	74.92	silver quality
liver	UBERON:0002107	74.77	gold quality
buccal mucosa cell	CL:0002336	74.64	gold quality
kidney	UBERON:0002113	74.30	gold quality
prefrontal cortex	UBERON:0000451	73.64	gold quality
ganglionic eminence	UBERON:0004023	73.55	gold quality
right lobe of liver	UBERON:0001114	73.42	gold quality
lower esophagus mucosa	UBERON:0035834	73.32	gold quality
secondary oocyte	CL:0000655	73.22	gold quality
skeletal muscle tissue	UBERON:0001134	73.07	gold quality
biceps brachii	UBERON:0001507	72.96	silver quality
cerebellar cortex	UBERON:0002129	72.89	gold quality
adrenal tissue	UBERON:0018303	72.85	gold quality
esophagus mucosa	UBERON:0002469	72.81	gold quality
jejunal mucosa	UBERON:0000399	72.80	gold quality
cerebellar hemisphere	UBERON:0002245	72.78	gold quality
cerebellum	UBERON:0002037	72.64	gold quality
colonic epithelium	UBERON:0000397	72.57	gold quality
oral cavity	UBERON:0000167	72.56	silver quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2927.09
E-MTAB-8142	yes	90.17
E-CURD-88	yes	38.92
E-MTAB-6701	yes	29.61
E-HCAD-4	yes	16.40
E-ANND-3	no	5.84
E-MTAB-6678	no	3.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

151 targeting L2HGDH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 21)

• encodes a putative mitochondrial protein with homology to FAD-dependent oxidoreductases; a mutant gene is accociated with L-2-hydroxyglutaric aciduria.propose to name the gene duranin (PMID:15385440)
• data indicate that l-2-hydroxyglutaric aciduria is due to a deficiency in l-2-hydroxyglutarate dehydrogenase (PMID:16005139)
• Indicate that 2-ketoglutaric acid is the metabolic precursor of L-2-hydrosyglutaric acid in L-2-hydroxyglutaric acid aciduria. (PMID:17876720)
• We successfully treated an adult patient with L-2-hydroxyglutaric aciduria using FAD and levocarnitine. (PMID:18362286)
• Report ten novel mutations in the L2HGDH gene in patients with L-2-hydroxyglutaric aciduria from different ethnic backgrounds. (PMID:18415700)
• Data show that L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene in exon 3 (c.292C–>T) and in exon 7 (c.887T–>A). (PMID:18671189)
• Report three unrelated Tunisian families containing seven patients with L2HGA mutations and inter-familial phenotype variability. (PMID:18780161)
• we present three novel mutations (Gln197X, Gly211Val and c.540+1 G>A), which increase the present deleterious collection of L2HGDH gene up to 35 mutationsthat we have compiled in this study. (PMID:19911013)
• analysis of genetic heterogeneity in D-2-hydroxyglutaric aciduria (PMID:20020533)
• The phenotype, including neurological manifestations and urinary levels of alpha-hydroxyglutarate, is reported and the phenotype-genotype relationship, is evaluated. (PMID:20052767)
• We did not find evidence for mutations in the genes D2HGDH and L2HGDH as an alternative mechanism for raised 2-hydroxyglutarate levels in brain tumours (PMID:20727073)
• Exonic mutations in the L2HGDH gene in Staffordshire bull terriers have been identified and associated with epilepsy. (PMID:20852250)
• L2HGDH mutation is not associated with glioblastoma. (PMID:21625441)
• Intragenic single nucleotide length polymorphisms and two extragenic microsatellites flanking the L2HGDH gene confirm the founder effect of c.241A>G mutation in the 14 studied cases. (PMID:24573090)
• modest increases in intracellular 2-HG in acute myeloid leukaemia cells, as seen with the rs11554137 SNP, might enhance chemoresistance, or promote acquisition of leukaemia-iniating mutations (PMID:24606602)
• c.845G>A (p.R282Q) in the exon 7 of the L2HGDH gene is associated with 2-hydroxyglutaric aciduria in Chinese family. (PMID:26829733)
• In this study, we describe a large pedigree from Pakistan showing multiple neurological symptoms. Homozygosity mapping and Sanger sequencing revealed a novel missense mutation in L2HGDH gene. (PMID:29458334)
• The mutations of the L2HGDH gene as the causes of L-2-hydroxyglutaric aciduria. (PMID:29980873)
• Two novel L2HGDH mutations were identified in a Chinese family with L-2-hydroxyglutaric aciduria. (PMID:30217188)
• MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome. (PMID:32101699)
• Loss of function variants in L2HGDH gene causing L-2-hydroxyglutaric aciduria. (PMID:37378753)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	l2hgdh	ENSDARG00000060500
mus_musculus	L2hgdh	ENSMUSG00000020988
rattus_norvegicus	L2hgdh	ENSRNOG00000004857
drosophila_melanogaster	L2HGDH	FBGN0032729
caenorhabditis_elegans		WBGENE00021564

Paralogs (10): YPEL3 (ENSG00000090238), PDPR (ENSG00000090857), YPEL1 (ENSG00000100027), FOXRED1 (ENSG00000110074), YPEL5 (ENSG00000119801), SARDH (ENSG00000123453), DMGDH (ENSG00000132837), AMT (ENSG00000145020), YPEL4 (ENSG00000166793), YPEL2 (ENSG00000175155)

Protein

Protein identifiers

L-2-hydroxyglutarate dehydrogenase, mitochondrial — Q9H9P8 (reviewed: Q9H9P8)

Alternative names: Duranin

All UniProt accessions (5): Q9H9P8, C9JVN9, G3V272, G3V3E2, G3V5S1

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Mitochondrion.

Tissue specificity. Widely expressed. Highly expressed in brain, testis and muscle. Expressed to a lower extent in lymphocytes, fibroblasts, keratinocytes, placenta, bladder, small intestine, liver and bone marrow.

Disease relevance. L-2-hydroxyglutaric aciduria (L2HGA) [MIM:236792] A rare autosomal recessive disorder clinically characterized by mild psychomotor delay in the first years of life, followed by progressive cerebellar ataxia, dysarthria and moderate to severe intellectual disability. Diagnosis is based on the presence of an excess of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Was named ‘duranin’ in honor of Marinus Duran, who first described L-2-hydroxyglutaric aciduria.

Similarity. Belongs to the L2HGDH family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H9P8-1	1	yes
Q9H9P8-2	2

RefSeq proteins (8): NP_001412141, NP_001412142, NP_001412143, NP_001412144, NP_001412145, NP_001412146, NP_001412147, NP_079160* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006076	FAD-dep_OxRdtase	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily

Pfam: PF01266

Enzyme classification (BRENDA):

• EC 1.1.99.2 — L-2-hydroxyglutarate dehydrogenase (BRENDA: 5 organisms, 24 substrates, 2 inhibitors, 13 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(S)-2-HYDROXYGLUTARATE	0.24–1.7	3
NAD+	0.2–5.3	3
L-2-HYDROXYGLUTARATE	4–13.3	2
(R)-2-HYDROXYGLUTARATE	15	1
2-OXOGLUTARATE	0.12	1
NADH	0.14	1

Catalyzed reactions (Rhea), 1 shown:

• (S)-2-hydroxyglutarate + A = 2-oxoglutarate + AH2 (RHEA:21252)

UniProt features (18 total): sequence variant 11, modified residue 3, splice variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9P8-F1	88.26	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 104, 155, 173

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-880009	Interconversion of 2-oxoglutarate and 2-hydroxyglutarate
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 162 (showing top): GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, GOBP_2_OXOGLUTARATE_METABOLIC_PROCESS, PARENT_MTOR_SIGNALING_UP, GOCC_ORGANELLE_INNER_MEMBRANE, GEORGES_TARGETS_OF_MIR192_AND_MIR215, TOYOTA_TARGETS_OF_MIR34B_AND_MIR34C, GOCC_ORGANELLE_ENVELOPE, DUTERTRE_ESTRADIOL_RESPONSE_24HR_UP, LEE_BMP2_TARGETS_DN, MTOR_UP.V1_DN, PRC1_BMI_UP.V1_DN

GO Biological Process (2): 2-oxoglutarate metabolic process (GO:0006103), small molecule metabolic process (GO:0044281)

GO Molecular Function (3): (S)-2-hydroxyglutarate dehydrogenase activity (GO:0047545), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on CH-OH group of donors (GO:0016614)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dicarboxylic acid metabolic process	1
metabolic process	1
oxidoreductase activity, acting on CH-OH group of donors	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
L2HGDH	D2HGDH	Q8N465	984
L2HGDH	IDH2	P48735	878
L2HGDH	IDH1	O75874	716
L2HGDH	MDH2	P40926	643
L2HGDH	ADHFE1	Q8IWW8	617
L2HGDH	FH	P07954	606
L2HGDH	SLC25A1	P53007	592
L2HGDH	OGDH	Q02218	518
L2HGDH	LDHA	P00338	506
L2HGDH	SUCLA2	Q9P2R7	489
L2HGDH	ETFDH	Q16134	488
L2HGDH	BCAT1	P54687	472
L2HGDH	BCKDHB	P21953	467
L2HGDH	SDHA	P31040	462
L2HGDH	SUCLG1	P53597	462

IntAct

45 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
COQ5	COQ9	psi-mi:“MI:0914”(association)	0.590
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
ITGB8	GET1	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
HMGCL	DBT	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
ATL3	SNX14	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
SCARB2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
COQ5	ACOT7	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	ACOT7	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	BTAF1	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
L2HGDH	A2ML1	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
SCGN	CNOT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (77): A2ML1 (Affinity Capture-MS), TGM1 (Affinity Capture-MS), LCN2 (Affinity Capture-MS), GM2A (Affinity Capture-MS), CTSV (Affinity Capture-MS), IVL (Affinity Capture-MS), KLK10 (Affinity Capture-MS), L2HGDH (Affinity Capture-MS), L2HGDH (Affinity Capture-MS), L2HGDH (Affinity Capture-MS), L2HGDH (Affinity Capture-MS), A2ML1 (Affinity Capture-MS), LCN2 (Affinity Capture-MS), IVL (Affinity Capture-MS), KLK10 (Affinity Capture-MS)

ESM2 similar proteins: A6QLU1, A7DZP8, A7MBI3, A7SMW7, A8X2R1, B0S6C5, B9FK36, O14400, P00927, P05165, P0DTA4, P14882, P17569, P32191, P35571, P43304, P43799, P54886, P54889, P54982, P78820, P90795, Q00955, Q0J954, Q16881, Q17828, Q2TAF8, Q38970, Q4R755, Q54QC1, Q5BLE8, Q5R4M8, Q5R9N7, Q61SU7, Q64521, Q86VQ6, Q86WA8, Q8H191, Q8S6N5, Q8SR40

Diamond homologs: A0A011QK89, A0A0M7LBC1, A0A5Y6MCT2, A4J9Z5, A7SMW7, A8X2R1, A9A9W1, B7N6P4, P37339, Q55GI5, Q58018, Q5R9N7, Q91YP0, Q9H9P8, Q9LES4, Q9N4Z0, S2DJ52, A7MBI3, A3PBD7, A8G3D1, A0A0R3K2G2, P47285, Q1H1H9, Q1GXL1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

316 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	12
Uncertain significance	136
Likely benign	73
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028352	NM_024884.3(L2HGDH):c.903T>G (p.Tyr301Ter)	Pathogenic
1070154	NC_000014.8:g.(?50778709)(50778888_?)del	Pathogenic
1299481	NM_024884.3(L2HGDH):c.959del (p.Asp320fs)	Pathogenic
1339478	NM_024884.3(L2HGDH):c.140+726del	Pathogenic
1429237	NM_024884.3(L2HGDH):c.418G>C (p.Ala140Pro)	Pathogenic
1448939	NM_024884.3(L2HGDH):c.853del (p.Tyr285fs)	Pathogenic
1608	NM_024884.3(L2HGDH):c.1115del (p.Met372fs)	Pathogenic
1609	NM_024884.3(L2HGDH):c.906+1G>T	Pathogenic
1610	NM_024884.3(L2HGDH):c.164G>A (p.Gly55Asp)	Pathogenic
2026101	NM_024884.3(L2HGDH):c.944del (p.Phe315fs)	Pathogenic
2086204	NM_024884.3(L2HGDH):c.256+2T>A	Pathogenic
211348	NM_024884.3(L2HGDH):c.465del (p.Gly156fs)	Pathogenic
2137582	NM_024884.3(L2HGDH):c.751C>T (p.Arg251Ter)	Pathogenic
2137583	NM_024884.3(L2HGDH):c.241A>G (p.Lys81Glu)	Pathogenic
2152204	NM_024884.3(L2HGDH):c.178G>A (p.Gly60Arg)	Pathogenic
2426898	NC_000014.8:g.(?50750569)(50750771_?)del	Pathogenic
2426899	NC_000014.8:g.(?50760813)(50768906_?)del	Pathogenic
2637446	NM_024884.3(L2HGDH):c.1081del (p.Ala361fs)	Pathogenic
30793	NM_024884.3(L2HGDH):c.1003C>T (p.Arg335Ter)	Pathogenic
3238838	NM_024884.3(L2HGDH):c.169G>A (p.Gly57Arg)	Pathogenic
3243997	NC_000014.8:g.(?50734451)(50734648_?)del	Pathogenic
3243998	NC_000014.8:g.(?50732056)(50732227_?)del	Pathogenic
3689720	NM_024884.3(L2HGDH):c.427C>T (p.Gln143Ter)	Pathogenic
3721504	NM_024884.3(L2HGDH):c.802G>T (p.Glu268Ter)	Pathogenic
435701	NM_024884.3(L2HGDH):c.1015del (p.Arg339fs)	Pathogenic
4849083	NC_000014.8:g.(50745273_50750588)_(50750752_50760832)del	Pathogenic
580563	NM_024884.3(L2HGDH):c.208C>T (p.Arg70Ter)	Pathogenic
831656	NC_000014.9:g.(?50267733)(50269350_?)del	Pathogenic
863865	NM_024884.3(L2HGDH):c.829C>T (p.Arg277Ter)	Pathogenic
873014	NM_024884.3(L2HGDH):c.408+1G>C	Pathogenic

SpliceAI

2448 predictions. Top by Δscore:

Variant	Effect	Δscore
14:50247043:AGCT:A	donor_gain	1.0000
14:50247044:G:C	donor_gain	1.0000
14:50247083:T:TA	donor_gain	1.0000
14:50247250:GCCC:G	acceptor_gain	1.0000
14:50247251:CCC:C	acceptor_gain	1.0000
14:50247251:CCCC:C	acceptor_gain	1.0000
14:50247252:CC:C	acceptor_gain	1.0000
14:50247252:CCC:C	acceptor_gain	1.0000
14:50247253:CC:C	acceptor_gain	1.0000
14:50247254:C:CA	acceptor_loss	1.0000
14:50247254:C:CC	acceptor_gain	1.0000
14:50247255:T:C	acceptor_loss	1.0000
14:50265487:CCA:C	acceptor_gain	1.0000
14:50265488:CAC:C	acceptor_gain	1.0000
14:50265490:C:CC	acceptor_gain	1.0000
14:50268852:T:TA	donor_gain	1.0000
14:50269046:A:AC	donor_gain	1.0000
14:50269047:C:CC	donor_gain	1.0000
14:50283865:GCTTA:G	donor_loss	1.0000
14:50283866:CTTAC:C	donor_loss	1.0000
14:50283867:TTACC:T	donor_loss	1.0000
14:50283868:TACCA:T	donor_loss	1.0000
14:50283869:A:AC	donor_gain	1.0000
14:50283870:C:CC	donor_gain	1.0000
14:50283870:CCAT:C	donor_gain	1.0000
14:50284030:GACC:G	acceptor_gain	1.0000
14:50284032:CC:C	acceptor_gain	1.0000
14:50284033:CC:C	acceptor_gain	1.0000
14:50284033:CCTGA:C	acceptor_loss	1.0000
14:50284034:C:CC	acceptor_gain	1.0000

AlphaMissense

3002 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:50269224:C:G	R282P	0.996
14:50294209:A:G	L149P	0.996
14:50302146:G:C	N93K	0.996
14:50302146:G:T	N93K	0.996
14:50267877:G:C	H314D	0.995
14:50267887:G:C	F310L	0.995
14:50267887:G:T	F310L	0.995
14:50267889:A:G	F310L	0.995
14:50269295:A:C	C258W	0.995
14:50294245:A:G	L137P	0.995
14:50302086:A:C	C113W	0.995
14:50284024:C:G	A184P	0.994
14:50302143:A:C	S94R	0.994
14:50302143:A:T	S94R	0.994
14:50302145:T:G	S94R	0.994
14:50302967:G:T	A64D	0.994
14:50247122:G:T	A443D	0.993
14:50247139:A:C	N437K	0.993
14:50247139:A:T	N437K	0.993
14:50247142:T:A	R436S	0.993
14:50247142:T:G	R436S	0.993
14:50302098:T:A	K109N	0.993
14:50302098:T:G	K109N	0.993
14:50302133:G:C	H98D	0.993
14:50267909:A:T	V303D	0.992
14:50269297:A:G	C258R	0.992
14:50284023:G:T	A184D	0.992
14:50302017:C:A	K136N	0.992
14:50302017:C:G	K136N	0.992
14:50247125:G:T	A442D	0.991

dbSNP variants (sampled 300 via entrez): RS1000073329 (14:50304520 C>T), RS1000143238 (14:50306154 G>A), RS1000180919 (14:50253665 G>C), RS1000238315 (14:50301072 C>T), RS1000287528 (14:50312541 G>A,C), RS1000314150 (14:50259924 T>C), RS1000319279 (14:50288592 G>A), RS1000346807 (14:50288789 G>T), RS1000423216 (14:50266325 T>C), RS1000446339 (14:50278087 C>T), RS1000458111 (14:50259951 G>A), RS1000565441 (14:50310162 T>C), RS1000589379 (14:50270907 T>C), RS1000591823 (14:50301520 C>A), RS1000626547 (14:50270687 T>C)

Disease associations

OMIM: gene MIM:609584 | disease phenotypes: MIM:236792, MIM:616559

GenCC curated gene-disease

Disease	Classification	Inheritance
L-2-hydroxyglutaric aciduria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): L-2-hydroxyglutaric aciduria (MONDO:0009370), Noonan syndrome 9 (MONDO:0014691)

Orphanet (2): L-2-hydroxyglutaric aciduria (Orphanet:79314), Noonan syndrome (Orphanet:648)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001272	Cerebellar atrophy
HP:0001285	Spastic tetraparesis
HP:0002062	Abnormal pyramidal tract morphology
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002171	Gliosis
HP:0002283	Global brain atrophy
HP:0002352	Leukoencephalopathy
HP:0002376	Developmental regression
HP:0002381	Aphasia
HP:0002383	Infectious encephalitis
HP:0003593	Infantile onset
HP:0004375	Neoplasm of the nervous system
HP:0007256	Abnormal pyramidal sign
HP:0007258	Severe demyelination of the white matter
HP:0007360	Aplasia/Hypoplasia of the cerebellum
HP:0007371	Corpus callosum atrophy
HP:0010864	Severe intellectual disability
HP:0040144	L-2-hydroxyglutaric aciduria
HP:0040147	L-2-hydroxyglutaric acidemia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002312_10	Periodontal disease-related phenotype (Socransky)	8.000000e-06
GCST006624_98	Systolic blood pressure	1.000000e-25
GCST007876_97	Estimated glomerular filtration rate	3.000000e-08
GCST008058_137	Estimated glomerular filtration rate	3.000000e-15
GCST008059_16	Estimated glomerular filtration rate	1.000000e-15
GCST008747_174	Estimated glomerular filtration rate	8.000000e-09
GCST008747_77	Estimated glomerular filtration rate	2.000000e-08
GCST012020_193	Serum metabolite levels	2.000000e-11
GCST012021_118	Serum metabolite levels	2.000000e-11
GCST90013405_112	Liver enzyme levels (alanine transaminase)	3.000000e-25

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression	2
bisphenol S	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
alpha-hydroxyglutarate	increases abundance	1
benzo(e)pyrene	increases methylation	1
acipimox	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Coumestrol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Mercuric Chloride	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2AQ	HAP1 L2HGDH (-) 2	Cancer cell line	Male
CVCL_E2AR	HAP1 L2HGDH (-) 3	Cancer cell line	Male
CVCL_E2AS	HAP1 L2HGDH (-) 4	Cancer cell line	Male
CVCL_E2AT	HAP1 L2HGDH (-) 5	Cancer cell line	Male
CVCL_XQ05	HAP1 L2HGDH (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.