IVD

protein-coding

isovaleryl-CoA dehydrogenase, the group of Acyl-CoA dehydrogenase family

Gene summary

Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

MANE transcript

NM_002225.5

Inheritance

ClinVar variants

P:207U:160B:212

Top phenotype

Isovaleric acidemia

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr15:40,405,485-40,435,947

External References & Databases

Ensembl (ENSG00000128928)

Transcript & Mutation Effects

hg38 • Region Span ~30.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isovaleric acidemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: Orphanet

isovaleric acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: Myriad Women's Health

isovaleric acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: Natera

isovaleric acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: G2P

isovaleric acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: ClinGen

The relationship between IVD and isovaleric acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of April, 2019. Isovaleric acidemia (IVA) is an inborn error of leucine metabolism characterized by an accumulation of isovaleryl-CoA derivatives in cells, blood and urine. Clinical presentation varies widely from acute neonatal to chronic intermittent and can be detected by newborn screening. Variation in IBD were first identified in humans with the disease as early as 1985 (Ikeda et al., PMID 3863140). To date, over 50 unique variants (missense, nonsense, frameshift, splicing) have been reported (Sakamoto et al., 2015; PMID 26018748). This gene-disease relationship is supported by biochemical assays, in vitro assays, and a mouse model. In summary, IVD is definitively associated with autosomal recessive isovaleric acedmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

isovaleric acidemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: Labcorp Genetics (formerly Invitae)

isovaleric acidemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009475

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Isovaleric acidemiaAR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical

Rationale: Medical/dietary treatment (eg, with l-carnitine, glycine, and leucine restricted/low protein diet) can be effective; Specific measures can be taken to prevent severe sequelae of acute metabolic decompensation

Refs: 5229850; 4378266; 4166104; 692626; 6630517; 3863140; 3139936; 3137519; 2063866; 15486829; 20142522; 20301313; 20662350; 20807522; 21207059; 21335445; 22004070; 22350545; 22960500; 23063737

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IVD variants in ClinVar

8 Conditions Cataloged

Isovaleryl-CoA dehydrogenase deficiencyTotal: 672

not providedTotal: 88

not specifiedTotal: 77

Inborn genetic diseasesTotal: 49

IVD-related disorderTotal: 33

Isovaleric acidemia, type ITotal: 2

Isovaleric acidemia, type IIITotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002225.5. 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			3 clinvar	206 clinvar		209
missense	3 clinvar	72 clinvar	154 clinvar	4 clinvar	1 clinvar	234
nonsense	7 clinvar	16 clinvar				23
start loss		2 clinvar	1 clinvar			3
frameshift	27 clinvar	37 clinvar		1 clinvar		65
splice donor/acceptor (+/-2bp)	11 clinvar	32 clinvar	2 clinvar			45
Total	48	159	160	211	1	579

Highest pathogenic variant AF is 0.0009013999

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002225.5	RefSeq	NP_002216.3	12	MANE Select
ENST00000487418.8	Ensembl	ENSP00000418397.3	12	MANE Select
NM_001159508.3	RefSeq	NP_001152980.2	11	Standard
NM_001354597.3	RefSeq	NP_001341526.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
Valproic Acid Pathway, Pharmacokinetics
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency

Biological Process

leucine catabolic process
branched-chain amino acid catabolic process
fatty acid beta-oxidation using acyl-CoA dehydrogenase

Molecular Function

protein binding
isovaleryl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000487418
Coding exons: 12
Length: 30461
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 65
Defined: 125748
p: 0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.349	231	246	0.937	0.0000148	2785
Missense (PolyPhen)		82	107.9	0.75998		1199
Synonymous	0.222	99	102	0.972	0.00000639	850
Loss of Function	0.243	22	23.3	0.946	0.00000125	255

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00036	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Isovaleric acidemia (IVA) [MIM:243500]: A metabolic disorder characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma. The acute neonatal form leads to massive metabolic acidosis from the first days of life and rapid death. {ECO:0000269|PubMed:2063866, ECO:0000269|PubMed:22004070, ECO:0000269|PubMed:22350545, ECO:0000269|PubMed:23587913, ECO:0000269|PubMed:28535199, ECO:0000269|PubMed:9665741}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.462

Intolerance Scores

LoFtool: 0.154
RVIS EVS: -0.29
RVIS percentile EVS: 33.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.555

Gene Damage Prediction

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